Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors

ABSTRACT

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula ##STR1## wherein each T is a substituent group; x is 0, 1, or 2; the group D represents ##STR2## the group R6 represents variety of possible substituent groups on the carbon chain between D and G, and the group G represents M, ##STR3## in which M represents --CO 2  H, --CON(R 11 ) 2 , or --CO 2  R 12 , and R 13  represents any of the side chains of the 19 noncyclic naturally occurring amino acids.

This application is a continuation of Ser. No. 08/436,490 filed Jun. 5,1995, abandoned, which is a continuation of Ser. No. 08/339,846 filedNov. 15, 1994, abandoned.

FIELD

This invention relates to enzyme inhibitors, and more particularly, tonovel 4-biarylbutyric or 5-biarylpentanoic acid compounds or derivativesthereof useful for inhibiting matrix metalloproteases.

BACKGROUND

The matrix metalloproteases (aka. matrix metalloendoproteinases or MMPs)are a family of zinc endoproteinases which include, but are not limitedto, interstitial collagenase (aka. MMP-1), stromelysin (aka.proteoglycanase, transin, or MMP-3), gelatinase A (aka. 72kDa-gelatinase or MMP-2) and gelatinase B (aka. 95 kDa-gelatinase orMMP-9). These MMPs are secreted by a variety of cells includingfibroblasts and chondrocytes, along with natural proteinatiousinhibitors known as TIMPs (Tissue Inhibitor of MetalloProteinase).

All of these MMPs are capable of destroying a variety of connectivetissue components of articular cartilage or basement membranes. Each MMPis secreted as an inactive proenzyme which must be cleaved in asubsequent step before it is able to exert its own proteolytic activity.In addition to the matrix destroying effect, certain of these MMPs suchas MMP-3 have been implemented as the in vivo activator for other MMPssuch as MMP-1 and MMP-9 (A. Ho, H. Nagase, Arch Biochem Biophys., 267,211-16 (1988); Y. Ogata, J. J. Enghild, H. Nagase, J. Biol. Chem., 267,3581-84 (1992)). Thus, a cascade of proteolytic activity can beinitiated by an excess of MMP-3. It follows that specific MMP-3inhibitors should limit the activity of other MMPs that are not directlyinhibited by such inhibitors.

It has also been reported that MMP-3 can cleave and thereby inactivatethe endogenous inhibitors of other proteinases such as elastase (P. G.Winyard, Z. Zhang, K. Chidwick, D. R. Blake, R. W. Carrell G., Murphy,FEBS Letts., 279, 1, 91-94 (1991)). Inhibitors of MMP-3 could thusinfluence the activity of other destructive proteinases by modifying thelevel of their endogenous inhibitors.

A number of diseases are thought to be mediated by excess or undesiredmatrix-destroying metalloprotease activity or by an imbalance in theratio of the MMPs to the TIMPS. These include: a) osteoarthritis(Woessner, et al., J. Biochelogical Chem., 259(6), 3633-3638 (1984); J.Rheumatol., 10, 852-860 (1883)), b) rheumatoid arthritis (D. E. Mullins,et al., Biochim. Biophys. Acta, 695, 117-214 (1983); Arthritis andRheumatism, 20, 1231-1239 (1977); Arthritis and Rheumatism, 34,1076-1105 (1991)), c) septic arthritis (R. J. Williams, et al., Arthr.Rheum., 33, 533-41 (1990)), d) tumor metastasis (R. Reich, et al.,Cancer Res., 48, 3307-3312 (1988), and L M. Matrisian, et al., Proc.Nat'l. Acad. Sci., USA, 83, 9413-7 (1986)), e) periodontal diseases (C.M. Overall, et al., J. Periodontal Res., 22, 81-88 (1987)), f) cornealulceration (F. R. Burns, et al., Invest. Opthalmol., 30, 1569-1575(1989)), g) proteinuria (W. H. Baricos, et al., Biochem. J., 254,609-612 (1988)), h) coronary thrombosis from atherosclerotic plaquerupture (A. M. Henney, et al., Proc. Nat'l. Acad. Sci. USA, 88,8154-8158 (1991)), i) aneurysmal aortic disease (N. Vine and J. T.Powell, Clin. Sci., 81, 233-9 (1991)), j) birth control (J. F. Woessner,et al., Steroids, 54, 491-499 (1989)), k) dystrophobic epidermolysisbullosa (A. Kronberger, et al., J. Invest. Dermatol., 79, 208-211(1982)), and l) degenerative cartilage loss following traumatic jointinjury, conditions leading to inflammatory responses, osteopeniasmediated by MMP activity, tempero mandibular joint disease, demyelatingdiseases of the nervous system, etc. (J. Neurochem., 50, 688-694(1988)).

The need for new therapies is especially important in the case ofarthritic diseases. The primary disabling effect of oeteoarthritis (OA),rheumatoid arthritis (RA) and septic arthritis is the progressive lossof articular cartilage and thereby normal joint function. No marketedpharmaceutical agent is able to prevent or slow this cartilage loss,although nonsteroidal antiinflammatory drugs (NSAIDs) have been given tocontrol pain and swelling. The end result of these diseases is totalloss of joint function which is only treatable by joint replacementsurgery. MMP inhibitors are expected to halt or reverse the progressionof cartilage loss and obviate or delay surgical intervention.

Several inhibitors of MMPs have been described in the literature. See,for example, U.S. Pat. No. 4,599,361; U.S. Pat. No. 5,190,937; EP 0574758 A1, published Dec. 22, 1993; EP 026 436 A1 published Aug. 3, 1988;and EP 0520 573 A1, published Dec. 30, 1992. These compounds havepeptide backbones with a zinc complexing group (hydroxamic acid, thiol,carboxylic acid or phosphinic acid) at one end and a variety ofsidechains, both those found in the natural amino acids as well as thosewith more novel functional groups. Such small peptides are usuallypoorly absorbed, exhibiting low oral bioavailability. They are alsosubject to rapid proteolytic metabolism, thus having short half lives.See, for example, a search for orally active peptide-based renininhibitors in which the best compound had a bioavailability of only 14%in monkeys: Saul H. Rosenberg, et al., J. Med. Chem., 36, 449-459(1993).

Certain 3-biphenoylpropanoic and 4-biaryloylbutanoic acids are describedin the literature as anti-inflammatory, anti-platelet aggregation,anti-phlogistic, anti-proliferative, hypolipidemic, antirheumatic,analgesic, and hypocholesterolemic agents. In none of these examples isa reference made to MMP inhibition as a mechanism for the claimedtherapeutic effect. Certain related compounds are also used asintermediates in the preparation of liquid crystals.

Specifically U.S. Pat. No. 3,784,701 claims certain substitutedbenzoylpropionic acids to treat inflammation and pain. These compoundsinclude 3-biphenoylpropanoic acid (aka fenbufen) shown below. ##STR4##

R. G. Child, et al., J. Pharm. Sci., 66, 466-476 (1977) describesstructure-activity relationships of several analogs of fenbufen. Theseinclude several compounds in which the biphenyl ring system issubstituted or the propanoic acid portion is substituted with phenyl,halogen, hydroxyl or methyl, or the carboxylic acid or carbonylfunctions are converted to a variety of derivatives. No compounds aredescribed which contain a 4'-substituted biphenyl and a substitutedpropanoic acid portion combined in one molecule. The phenyl (compoundsXVII) and methyl (compound XLVIII) substituted compounds shown belowwere described as inactive. ##STR5##

K. K. Kameo, et al., Chem. Pharm. Bull., 36, 2050-2060 and JP patent62132825 describe certain substituted 3-biphenoylpropionic acidderivatives and analogs thereof including the following. Variouscompounds with other substituents on the propionic acid portion aredescribed, but they do not contain biphenyl residues. ##STR6##

H. Cousse, et al., Eur. J. Med. Chem., 22, 45-57 (1987) describe thefollowing methyl and methylene substituted 3-biphenoylpropanoic and-propenoic acids. The corresponding compounds in which the carbonyl isreplaced with either CHOH or CH₂ are also described. ##STR7##

German Patent Application No. 19 57 750 of Tomae also describes certainof the above methylene substituted biphenoylpropanoic acids.

M. A. El-Hashsh, et al., Revue Roum. Chim., 23, 1581-1588 (1978)describe products derived from β-aroyl-acrylic acid epoxides includingthe following biphenyl compound. No compounds substituted on thebiphenyl portion are described. ##STR8##

T. Kitamura, et al., Japanese Patent Application No. 84-65795 840404describes certain biphenyl compounds used as intermediates for theproduction of liquid crystals including the following. The biphenyl isnot substituted in these intermediates. ##STR9##

German Patent No. 28 54 475 uses the following compound as anintermediate. The biphenyl group is not substituted. ##STR10##

A. Sammou, et al., Egypt J. Chem., 15, 311-327 (1972) and J. Couquelet,et al., Bull. Soc. Chim. Fr., 9, 3196-9 (1971) describe certaindialkylamino substituted biphenoylpropanoic acids including thefollowing. In no case is the biphenyl group substituted. ##STR11##

It would be desirable to have effective MMP inhibitors which possessimproved bioavailablity and biological stability relative to thepeptide-based compounds of the prior art, and which can be optimized foruse against particular target MMPs. Such compounds are the subject ofthe present application.

SUMMARY

This invention relates to compounds having matrix metalloproteaseinhibitory activity and the generalized formula:

    (T).sub.x A-B-D-E-G                                        (I)

In the above generalized formula (I), (T)_(x) A represents a substitutedor unsubstituted aromatic 6-membered ring or heteroaromatic 5-6 memberedring containing 1-2 atoms of N, O, or S. T represents one or moresubstituent groups, the subscript x represents the number of suchsubstituent groups, and A represents the aromatic or heteroaromaticring, designated as the A ring or A unit. When N is employed inconjunction with either S or O in the A ring, these heteroatoms areseparated by at least one carbon atom.

The substituent group(s) T are independently selected from the groupconsisting of halogen; alkyl; haloalkyl; alkenyl; alkynyl; --(CH₂)_(p) Qin which p is 0 or an integer of 1-4; and -alkenyl-Q in which thealkenyl moiety comprises 2-4 carbons. Q in the latter two groups isselected from the group consisting of aryl, heteroaryl, --CN, --CHO,--NO₂, --CO₂ R², --OCOR², --SOR³, --SO₂ R³, --CON(R²)₂, --SO₂ N(R²)₂,--COR², --N(R²)₂, --N(R²)COR², --N(R²)CO₂ R³, --N(R²)CON(R²)₂, --CHN₄,--OR⁴, and --SR⁴. In these formulae R² represents H, alkyl, aryl,heteroaryl, arylalkyl, or heteroaryl-alkyl; R3 represents alkyl, aryl,heteroaryl, arylalkyl, or heteroaryl-alkyl; and R4 represents H, alkyl,aryl, heteroaryl, arylalkyl, heteroaryl-alkyl, alkenyl, alkynyl,haloalkyl, acyl, or alkyleneoxy or polyalkyleneoxy terminated with H,alkyl, or phenyl. Unsaturation in a moiety which is attached to Q orwhich is part of Q is separated from any N, O, or S of Q by at least onecarbon atom. The A ring may be unsubstituted or may carry up to 2substituents T. Accordingly, the subscript x is 0, 1, or 2.

In the generalized formula (I), B represents an aromatic 6-membered ringor a heteroaromatic 5-6 membered ring containing 1-2 atoms of N, O, orS. It is referred to as the B ring or B unit. When N is employed inconjunction with either S or O in the B ring, these heteroatoms areseparated by at least one carbon atom.

In the generalized formula (I), D represents ##STR12##

In the generalized formula (I), E represents a chain of n carbon atomsbearing m substituents R⁶, in which the R⁶ groups are independentsubstituents, or constitute spiro or nonspiro rings. Rings may be formedin two ways: a) two groups R⁶ are joined, and taken together with thechain atom(s) to which the two R6 group(s) are attached, and anyintervening chain atoms, constitute a 3-7 membered ring, or b) one groupR⁶ is joined to the chain on which this one group R⁶ resides, and takentogether with the chain atom(s) to which the R⁶ group is attached, andany intervening chain atoms, constitutes a 3-7 membered ring. The numbern of carbon atoms in the chain is 2 or 3, and the number m of R⁶substituents is an integer of 1-3. The number of carbons in the totalityof R⁶ groups is at least two.

Each group R⁶ is independently selected from the group consisting of:

alkyl, provided that if the A unit is phenyl, the B unit is phenylene, mis 1, and n is 2, then x is 1 or 2;

aryl, provided that if said A unit is phenyl, said B unit is phenylene,said aryl group is phenyl, n is 2, and m is 1 or 2, then x is 1 or 2;

heteroaryl;

arylalkyl;

heteroaryl-alkyl;

alkenyl;

aryl-substituted alkenyl;

heteraryl-substituted alkenyl;

alkynyl;

aryl-substituted alkynyl;

heteroaryl-substituted alkynyl;

--(CH₂)_(R) ⁷, wherein t is 0 or an integer of 1-5 and R⁷ is selectedfrom the group consisting of:

N-phthalimidoyl;

N-(1,2-naphthalenedicarboximidoyl);

N-(2,3-naphthalenedicarboximidoyl);

N-(1,8-naphthalenedicarboximidoyl);

N-indoloyl;

N-(2-pyrrolodinonyl);

N-succinimidoyl;

N-maleimidoyl;

3-hydantoinyl;

1,2,4-urazolyl;

amido;

urethane;

urea; and

nonaromatic substituted or unsubstituted heterocycles containing andconnected through a N atom, and comprising one additional O or S; and

amino;

and corresponding heteroaryl moieties in which the aryl portion of anaryl-containing R⁷ group comprises 4-9 carbons and at least one N, O, orS heteroatom, but with the proviso that when R⁷ is a nonaromaticheterocycle or an amino group, and t is 0, m is 1, and n is 2, then x is1 or 2; and

--(CH₂)_(v) ZR⁸ in which v is 0 or an integer of 1-4, Z represents##STR13## R⁸ is selected from the group consisting of: alkyl;

aryl;

heteroaryl;

arylalkyl;

heteroaryl-alkyl; and

--C(O)R⁹ in which R⁹ represents alkyl of at least two carbons, aryl,heteroaryl, arylalkyl, or heteroaryl-alkyl;

and with the further provisos that

when R⁸ is --C(O)R⁹, Z is S or O;

when Z is O, R⁸ may also be alkyleneoxy or polyalkyleneoxy terminatedwith H, alkyl, or phenyl; and

when said A unit is phenyl, said B unit is phenylene, m is 1, n is 2,and v is 0, then x is 1 or 2; and

trialkylsilyl-substituted alkyl.

Furthermore, aryl or heteroaryl portions of any of the T or R⁶ groupsoptionally may bear up to two substituents selected from the groupconsisting of --(CH₂)_(y) C(R¹¹)(R¹²)OH, --(CH₂)_(y) OR¹¹, --(CH₂)_(y)SR¹¹, --(CH₂)_(y) S(O)R¹¹, --(CH₂)_(y) S(O)₂ R¹¹, --(CH₂)_(y) SO₂N(R¹¹)₂, --(CH₂)_(y) N(R¹¹)₂, --(CH₂)_(y) N(R¹¹)COR¹², --OC(R¹¹)₂ O-- inwhich both oxygen atoms are connected to the aryl ring, --(CH₂)_(y)COR¹¹, --(CH₂)_(y) CON(R¹¹)₂, --(CH₂)_(y) CO₂ R¹¹, --(CH₂)_(y) OCOR¹¹,-halogen, --CHO, --CF₃, --NO₂, --CN, and --R¹², in which y is 0-4; R¹¹represents H or lower alkyl; and R¹² represents lower alkyl.

In the generalized formula (I), G represents --PO₃ H₂, --M ##STR14## inwhich M represents --CO₂ H, --CON(R¹¹)₂, or --CO₂ R¹², and R¹³represents any of the side chains of the 19 noncyclic naturallyoccurring amino acids. Pharmaceutically acceptable salts of thesecompounds are also within the scope of the invention.

In most related reference compounds of the prior art, the biphenylportion of the molecule is unsubstituted, and the propanoic or butanoicacid portion is either unsubstituted or has a single methyl or phenylgroup. Presence of the larger phenyl group has been reported to causeprior art compounds to be inactive as anti-inflammatory analgesicagents. See, for example, R. G. Child, et al., J. Pharm. Sci., 66,466-476 (1977) By contrast, it has now been found that compounds whichexhibit potent MMP inhibitory activity contain a substituent ofsignificant size on the propanoic or butanoic portion of the molecule.The biphenyl portions of the best MMP inhibitors also preferably containa substituent on the 4' position, although when the propanoic orbutanoic portions are optimally substituted, the unsubstituted biphenylcompounds of the invention have sufficient activity to be consideredrealistic drug candidates.

In addition to the above-described compounds, the invention also relatesto pharmaceutical compositions having matrix metalloprotease inhibitoryactivity, which compositions comprise a compound of the invention asdescribed above, and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a mammal to achievean effect, in which the effect is: alleviation of osteoarthritis,rheumatoid arthritis, septic arthritis, periodontal disease, cornealulceration, proteinuria, aneurysmal aortic disease, dystrophobicepidermolysis bullosa, conditions leading to inflammatory responses,osteopenias mediated by MMP activity, tempero mandibular joint disease,or demyelinating diseases of the nervous system; retardation of tumormetastasis or degenerative cartilage loss following traumatic jointinjury; reduction of coronary thrombosis from atherosclerotic plaquerupture; or improved birth control; the method comprising administeringan amount of a compound of the invention as described above which iseffective to inhibit the activity of at least one matrixmetalloprotease, resulting in achievement of the desired effect.

DETAILED DESCRIPTION

More particularly, the compounds of the present invention are materialshaving matrix metalloprotease inhibitory activity and the generalizedformula:

    (T).sub.x A-B-D-E-G                                        (I)

in which (T)_(x) A represents a substituted or unsubstituted aromatic orheteroaromatic moiety selected from the group consisting of: ##STR15##in which R¹ represents H or alkyl of 1-3 carbons.

In these structures, the aromatic ring is referred to as the A ring or Aunit, and each T represents a substituent group, referred to as a Tgroup or T unit. Substituent groups T are independently selected fromthe group consisting of: the halogens --F, --Cl, --Br, and --I; alkyl of1-10 carbons; haloalkyl of 1-10 carbons; alkenyl of 2-10 carbons;alkynyl of 2-10 carbons; --(CH₂)_(p) Q in which p is 0 or an integer1-4, and -alkenyl-Q in which the alkenyl moiety comprises 2-4 carbons. Qin each of the latter two groups is selected from the group consistingof aryl of 6-10 carbons; heteroaryl comprising 4-9 carbons and at leastone N, O, or S heteroatom; --CN; --CHO; --NO₂ ; --CO₂ R² ; --OCOR² ;--SOR³ ; --SO₂ R³ ; --CON(R²)₂ ; --SO₂ N(R²)₂ ; --C(O)R² ; --N(R²)₂ ;--N(R²)COR² ; --N(R²)CO₂ R³ ; --N(R²)CON(R²)₂ ; --CHN₄ ; --OR⁴ ; and--SR⁴. The groups R², R³, and R⁴ are defined as follows.

R² represents H; alkyl of 1-6 carbons; aryl of 6-10 carbons; heteroarylcomprising 4-9 carbons and at least one N, O, or S heteroatom; arylalkylin which the aryl portion contains 6-10 carbons and the alkyl portioncontains 1-4 carbons; or heteroarylalkyl in which the heteroaryl portioncomprises 4-9 carbons and at least one N, O, or S heteroatom and thealkyl portion contains 1-4 carbons.

R³ represents alkyl of 1-4 carbons; aryl of 6-10 carbons; heteroarylcomprising 4-9 carbons and at least one N, O, or S heteroatom; arylalkylin which the aryl portion contains 6-10 carbons and the alkyl portioncontains 1-4 carbons; or heteroarylalkyl in which the heteroaryl portioncomprises 4-9 carbons and at least one N, O, or S heteroatom and thealkyl portion contains 1-4 carbons.

R⁴ represents H; alkyl of 1-12 carbons; aryl of 6-10 carbons; heteroarylcomprising 4-9 carbons and at least one N, O, or S heteroatom; arylalkylin which the aryl portion contains 6-10 carbons and the alkyl portioncontains 1-4 carbons; heteroarylalkyl in which the heteroaryl portioncomprises 4-9 carbons and at least one N, O, or S heteroatom and thealkyl portion contains 1-4 carbons; alkenyl of 2-12 carbons; alkynyl of2-12 carbons; --(C_(q) H_(2q) O)_(r) R⁵ in which q is 1-3, r is 1-3, andR⁵ is H provided q is greater than 1, or R⁵ is alkyl of 1-4 carbons, orphenyl; --(CH₂)_(s) X in which s is 2-3 and X is halogen; or --C(O)R².

Any unsaturation in a moiety which is attached to Q or which is part ofQ is separated from any N, O, or S of Q by at least one carbon atom, andthe number of substituents, designated x, is 0, 1, or 2.

In the generalized formula (I), B represents an aromatic orheteroaromatic ring selected from the group consisting of: ##STR16## inwhich R¹ is defined as above. These rings are referred to as the B ringor B unit.

In the generalized formula (I), D represents the moieties ##STR17##

In the generalized formula (I), E represents a chain of n carbon atomsbearing m substituents R⁶, referred to as R⁶ groups or R⁶ units. The R⁶groups are independent substituents, or constitute spiro or nonspirorings. Rings may be formed in two ways: a) two groups R⁶ are joined, andtaken together with the chain atom(s) to which the two R6 group(s) areattached, and any intervening chain atoms, constitute a 3-7 memberedring, or b) one group R⁶ is joined to the chain on which this one groupR⁶ resides, and taken together with the chain atom(s) to which the R⁶group is attached, and any intervening chain atoms, constitutes a 3-7membered ring. The number n of carbon atoms in the chain is 2 or 3, andthe number m of R⁶ substituents is an integer of 1-3. The number ofcarbons in the totality of R⁶ groups is at least two.

Each group R⁶ is independently selected from the group consisting of thesubstituents listed below as items 1)-14).

1) An R⁶ group may be alkyl of 1-10 carbons, provided that if the A unitis phenyl, the B unit is phenylene, m is 1, n is 2, and the alkyl groupis located on the alpha carbon relative to the D unit, then x is 1 or 2.

2) An R⁶ group may be aryl of 6-10 carbons, provided that if the A unitis phenyl, the B unit is phenylene, the aryl group is phenyl, n is 2,and m is 1 or 2, then x is 1 or 2.

3) An R⁶ group may be heteroaryl comprising 4-9 carbons and at least oneN, O, or S heteroatom.

4) An R⁶ group may be arylalkyl in which the aryl portion contains 6-10carbons and the alkyl portion contains 1-8 carbons.

5) An R⁶ group may be heteroaryl-alkyl in which the heteroaryl portioncomprises 4-9 carbons and at least one N, O, or S heteroatom, and thealkyl portion contains 1-8 carbons;

6) An R⁶ group may be alkenyl of 2-10 carbons.

7) An R⁶ group may be aryl-alkenyl in which the aryl portion contains6-10 carbons and the alkenyl portion contains 2-5 carbons.

8) An R⁶ group may be heteroaryl-alkenyl in which the heteroaryl portioncomprises 4-9 carbons and at least one N, O, or S heteroatom and thealkenyl portion contains 2-5 carbons;

9) An R⁶ group may be alkynyl of 2-10 carbons.

10) An R⁶ group may be aryl-alkynyl in which the aryl portion contains6-10 carbons and the alkynyl portion contains 2-5 carbons.

11) An R⁶ group may be heteroaryl-alkynyl in which the heteroarylportion comprises 4-9 carbons and at least one N, O, or S heteroatom andthe alkynyl portion contains 2-5 carbons.

12) An R⁶ group may be --(CH₂)_(t) R⁷ in which t is 0 or an integer of1-5 and R⁷ is selected from the group consisting of ##STR18## as well ascorresponding heteroaryl moieties in which the aryl portion of anaryl-containing R⁷ group comprises 4-9 carbons and at least one N, O, orS heteroatom. In such R7 groups, Y represents O or S; R¹, R², and R³ areas defined above; and u is 0, 1, or 2; provided that when R⁷ is##STR19## and the A unit is phenyl, the B unit is phenylene, m is 1, nis 2, and t is 0, then x is 1 or 2.

13) An R⁶ group may be --(CH₂)_(v) ZR⁸ in which v is 0 or an integer of1 to 4; Z represents --S--, --S(O)--, --SO₂ --, or --O--; and R⁸ isselected from the group consisting of: alkyl of 1 to 12 carbons; aryl of6 to 10 carbons; heteroaryl comprising 4-9 carbons and at least one N,O, or S heteroatom; arylalkyl in which the aryl portion contains 6 to 12carbons and the alkyl portion contains 1 to 4 carbons; heteroaryl-alkylin which the aryl portion comprises 4-9 carbons and at least one N, O,or S heteroatom and the alkyl portion contains 1-4 carbons; --C(O)R⁹ inwhich R⁹ represents alkyl of 2-6 carbons, aryl of 6-10 carbons,heteroaryl comprising 4-9 carbons and at least one N, O, or Sheteroatom, or arylalkyl in which the aryl portion contains 6-10 carbonsor is heteroaryl comprising 4-9 carbons and at least one N, O, or Sheteroatom, and the alkyl portion contains 1-4 carbons, with theprovisos that

when R⁸ is --C(O)R⁹, Z is --S-- or --O--;

when Z is --O--, R⁸ may also be --(C_(q) H_(2q) O)_(r) R⁵ in which q, r,and R⁵ are as defined above; and

when the A unit is phenyl, the B unit is phenylene, m is 1, n is 2, andv is 0, then x is 1 or 2; and

14) An R⁶ group may be --CH₂)_(w) SiR¹⁰ ₃ in which w is an integer of 1to 3, and R¹⁰ represents alkyl of 1 to 2 carbons.

In addition, aryl or heteroaryl portions of any of the T or R⁶ groupsoptionally may bear up to two substituents selected from the groupconsisting of --(CH₂)_(y) C(R¹¹)(R¹²)OH, --(CH₂)_(y) OR¹¹, --(CH₂)_(y)SR¹¹, --(CH₂)_(y) S(O)R¹¹, --(CH₂)_(y) S(O)₂ R¹¹, --(CH₂)_(y) SO₂N(R¹¹)₂, --(CH₂)_(y) N(R¹¹)₂, --(CH₂)_(y) N(R¹¹)COR¹², --OC(R¹¹)₂ O-- inwhich both oxygen atoms are connected to the aryl ring, --(CH₂)_(y)COR¹¹, --(CH₂)_(y) CON(R¹¹)₂, --(CH₂)_(y) CO₂ R¹¹, --(CH₂)_(y) OCOR¹¹,-halogen, --CHO, --CF₃, --NO₂, --CN, and --R¹², in which y is 0-4; R¹¹represents H or alkyl of 1-4 carbons; and R¹² represents alkyl of 1-4carbons.

In the generalized formula (I), G represents --PO₃ H₂, --M, ##STR20## inwhich M represents --CO₂ H, --CON(R¹¹)₂, or --CO₂ R¹², and R¹³represents any of the side chains of the 19 noncyclic naturallyoccurring amino acids. Pharmaceutically acceptable salts of thecompounds falling within the generalized formula (I) are also within theinvention.

It is to be understood that as used herein, the term "alkyl" meansstraight, branched, cyclic, and polycyclic materials. The term"haloalkyl" means partially or fully halogenated alkyl groups such as--(CH₂)₂ Cl, --CF₃ and --C₆ F₁₃, for example.

The B ring of generalized formula (I) is a substituted or unsubstitutedaromatic or heteroaromatic ring, in which any substituents are groupswhich do not cause the molecule to fail to fit the active site of thetarget enzyme, or disrupt the relative conformations of the A and Brings, such that they would be detrimental. Such groups may be moietiessuch as lower alkyl, lower alkoxy, CN, NO₂, halogen, etc., but are notto be limited to such groups.

In one of its embodiments, the invention relates to compounds ofgeneralized formula (I) in which at least one of the units A, B, T, andR⁶ comprises a heteroaromatic ring. Preferred heteroaromaticring-containing compounds are those in which the heteroaryl groups areheteroaryl of 4-9 carbons comprising a 5-6 membered heteroaromatic ringcontaining O, S, or NR¹ when the ring is 5-membered, and N when saidring is 6-membered. Particularly preferred heteroaromaticring-containing compounds are those in which at least one of the A and Bunits comprises a thiophene ring. When A unit is thiophene, it ispreferably connected to B unit at position 2 and carries one substituentgroup T on position 5. When B Unit is thiophene, it is preferablyconnected through positions 2 and 5 to D and A units respectively.

In the generalized formula (I), the A and B rings are preferably phenyland phenylene, respectively, the A ring preferably bears at least onesubstituent group T preferably located on the position furthest from theposition of the A ring which is connected to the B ring, the D unit ispreferably a carbonyl group, and the G unit is preferably a carboxylgroup.

In another embodiment, the invention relates to compounds of generalizedformula (I), in the E unit of which n is 2 and m is 1. These compoundsthus possess two carbon atoms between the D unit and the G unit, andcarry one substituent on this two-carbon chain.

In another of its embodiments, the invention relates to compounds ofgeneralized formula (I) in which the A ring is a substituted orunsubstituted phenyl group, the B ring is p-phenylene, and aryl portionsof any aryl-containing T and R⁶ moieties contain only carbon in therings. These compounds thus contain no heteroaromatic rings.

In another of its embodiments, the invention relates to compounds ofgeneralized formula (I) in which m is 1 and R⁶ is an independentsubstituent. These compounds are materials which contain only a singlesubstituent R⁶ on the E unit, and this substituent in not involved in aring. Preferred compounds within this subset have the formula ##STR21##in which x is 1 or 2, and one substituent group T is located on the4-position of the A ring, relative to the point of attachment betweenthe A and B rings. Substituent group T of this subset is preferably thehalogens --Cl, --Br or I or is an ether --OR⁴. Most preferred compoundscontain only one substituent T on the 4-position of the A ring relativeto the attachment to B ring.

Preferred compounds of general formula (I) in which R⁶ is --(CH₂)_(t) R⁷have t as an integer of 1-5. Preferred compounds of general formula (I)in which R⁶ is --(CH₂)_(v) ZR⁸ have v as an integer of 1-4 and Z as--S-- or --O--. Preferred compounds of general formula (I) in which R⁶is alkyl contain 4 or more carbons in said alkyl and those in which R⁶is arylalkyl contain 2-3 carbons in the alkyl portion of said arylalkyl.

In another of its embodiments, the invention relates to compounds ofgeneralized formula (I) in which the number of substituents m on the Eunit is 2 or 3; and when m is 2, both groups R⁶ are independentsubstituents, or together constitute a spiro ring, or one group R⁶ is anindependent substituent and the other constitutes a spiro ring; and whenm is 3, two groups R⁶ are independent substituents and one group R⁶constitutes a ring, or two groups R6 constitute a ring and one group R6is an independent substituent, or three groups R6 are independentsubstituents. This subset therefore contains compounds in which the Eunit is di- or tri- substituted, and in the disubstituted case any ringsformed by one or both R⁶ groups are spiro rings, and in thetrisubstituted case, the R⁶ groups may form either spiro or nonspirorings.

In another of its embodiments, the invention relates to compounds ofgeneralized formula (I) in which the number of substituents m on the Eunit is 1 or 2; and when m is 1, the group R⁶ constitutes a nonspiroring; and when m is 2, both groups R⁶ together constitute a nonspiroring or one group R6 is an independent substituent and the otherconstitutes a nonspiro ring. This subset therefore contains compounds inwhich the E unit carries one or two substituents R⁶, and at least one ofthese substituents is involved in a nonspiro ring.

More particularly, representative compounds of generalized formula (I)in which one or more of the substituent groups R⁶ are involved information of nonspiro rings have E units of the following structures:##STR22## in which a is 0, 1, or 2; b is 0 or 1; c is 0 or 1; d is 0 or1; c+d is 0 or 1; e is 1-5; f is 1-4; g is 3-5; h is 2-4; i is 0-4; j is0-3; is 0-2; the total number of groups R⁶ is 0, 1, or 2; U representsO, S, or NR¹ ; and z is 1 or 2; Each group R¹⁴ is independently selectedfrom the group consisting of: alkyl of 1-9 carbons; arylalkyl in whichthe alkyl portion contains 1-7 carbons and the aryl portion contains6-10 carbons; alkenyl of 2-9 carbons; aryl-substituted alkenyl in whichthe alkenyl portion contains 2-4 carbons and the aryl portion contains6-10 carbons; alkynyl of 2-9 carbons; aryl-substituted alkynyl in whichthe alkynyl portion contains 2-4 carbons and the aryl portion contains6-10 carbons; aryl of 6-10 carbons; --COR² ; --CO₂ R³ ; --CON(R²)₂ ;--(CH₂)_(t) R⁷ in which t is 0 or an integer of 1-4; and --(CH₂)_(v) ZR⁸in which v is 0 or an integer of 1 to 3, and Z represents --S-- or--O--. R¹, R⁷, and R⁸ have been defined above.

Preferred compounds of generalized formula (I) in which one or more ofthe substituent groups R⁶ are involved in formation of nonspiro ringshave E units of the following structures: ##STR23## in which a, b, c, d,(c+d), e, g, i, k, the total number of groups R⁶, U, and R¹⁴ are asdefined above.

The more preferred compounds of generalized formula (I) in which one ormore of the substituent groups R⁶ are involved in formation of nonspirorings have the formula ##STR24## in which the subscript x is 1 or 2; onesubstituent T is located on the 4-position of the A ring, relative tothe point of attachment between the A and B rings; e is 2 or 3; and R¹⁴is as defined above.

The invention also relates to certain intermediates useful in thesynthesis of some of the claimed inhibitors. These intermediates arecompounds having the generalized formula ##STR25## in which E represents##STR26## T represents a substituent group, and x is 1 or 2.

Those skilled in the art will appreciate that many of the compounds ofthe invention exist in enantiomeric or diastereomeric forms, and that itis understood by the art that such stereoisomers generally exhibitdifferent activities in biological systems. This invention encompassesall possible stereoisomers which possess inhibitory activity against anMMP, regardless of their stereoisomeric designations, as well asmixtures of stereoisomers in which at least one member possessesinhibitory activity.

General Preparative Methods:

All the compounds of the present invention may be prepared by chemicalreactions and procedures which are known to the art, without thenecessity for undue experimentation. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing theinhibitors, with more detailed particular examples being presented belowin the experimental section describing the working examples.

All variable groups of these methods are as described in the genericdescription if they are not specifically defined below. The variablesubscript n is independently defined for each method. When a variablegroup with a given symbol (i.e. R⁶ or T) is used more than once in agiven structure, it is to be understood that each of these groups may beindependently varied within the range of definitions for that symbol.

General Method A--The compounds of this invention in which the rings Aand B are substituted phenyl and phenylene respectively are convenientlyprepared by use of a Friedel-Crafts reaction of a substituted biphenylII with an activated acyl- containing intermediate such as the succinicor glutaric anhydride derivative III in the presence of a Lewis acidcatalyst such as aluminum trichloride in an aprotic solvent such as1,1,2,2-tetrachloroethane. The well known Friedel-Crafts reaction can beaccomplished with use of many alternative solvents and acid catalysts asdescribed by E. Berliner, Org. React., 5, 229 (1949) and H. Heaney,Comp. Org. Synth., 2, 733 (1991). ##STR27##

If the anhydride III is monosubstituted or multiply-substituted in anunsymmetrical way, the raw product I often exists as a mixture ofisomers via attack of the anhydride from either of the two carbonyls.The resultant isomers can be separated into pure forms bycrystallization or chromatography using standard methods known to thoseskilled in the art.

This method is especially useful for the preparation of cyclic compoundsin which two R⁶ groups are connected in a methylene chain to form a 3-7member ring.

This method is also useful when double bonds are found either betweenC-2 and C-3 of a succinoyl chain (from maleic anhydride or1-cyclopentene-1,2-dicarboxylic anhydride, for example) or when a doublebond is found in a side chain, such as in the use of itaconic anhydrideas starting material to yield products in which two R⁶ groups as foundon one chain carbon together form an exo-methylene (═CH₂) group.

General Method B--Other active acyl derivatives such as the acidchloride IV can be used instead of anhydride III. The resultant esterproducts I-B are then hydrolyzed by aqueous base in a way known to thoseskilled in the art to yield the more potent acids I. ##STR28##

General Method C--Alternatively the compounds I can be prepared via areaction sequence involving mono-alkylation of a dialkyl malonate VIwith an alkyl halide to form intermediate VII, followed by alkylationwith a halomethyl biphenyl ketone VIII to yield intermediate IX.Compounds of structure IX are then hydrolyzed with aqueous base and thenheated to decarboxylate the malonic acid intermediate and yield I(Method C-1). By using one equivalent of aqueous base the esters I-Cwith R¹² as alkyl are obtained, and using more than two equivalents ofbase the acid compounds (R¹² =H) are obtained. Optionally, heat is notused and the diacid or acid-ester I-B is obtained. Alternatively, thediester intermediate IX can be heated with a strong acid such asconcentrated hydrochloric acid in acetic acid in a sealed tube at about110° C. for about 24 hr.

Alternatively, the reaction of VI with VIII can be conducted before thatwith the alkyl halide to yield the same IX (Method C-2).

Intermediates VIII are formed from biphenyls II in a Friedel-Craftreaction with haloacetyl halides such as bromoacetyl bromide orchloroacetyl chloride. Alternatively, the biphenyl can be reacted withacetyl chloride or acetic anhydride and the resultant producthalogenated with, for example, bromine to yield intermediates VIII(X=Br).

Method C has the advantage of yielding single regio isomers when MethodA yields mixtures. Method C is especially useful when the side chains R⁶contain aromatic or heteroaromatic rings that may participate inintramolecular acylation reactions to give side products if Method Awere to be used. This method is also very useful when the R⁶ groupadjacent to the carboxyl of the final compound contains heteroatoms suchas oxygen, sulfur, or nitrogen, or more complex functions such as imiderings. ##STR29##

General Method D--Especially useful is the use of chiral HPLC toseparate the enantiomers of racemic product mixtures (see, for example,D. Arlt, B. Boemer, R Grosser and W. Lange, Angew. Chem. Int. Ed. Engl.30 (1991) No. 12). The compounds of this invention are prepared as pureenantiomers by use of a chiral auxiliary route--see, for example: D. A.Evans, Aldrichimica Acta, 15(2), 23 (1982) and other similar referencesknown to one skilled in the art.

D-1. Acid halide X is reacted with the lithium salt of chiral auxiliaryXI (R is often isopropyl or benzyl) to yield intermediate XII, which inturn is akylated at low temperatures (typically under -50° C.) withhalo-tert-butylacetyl compound XIII to yield pure isomer XIV. The use ofopposite chirality XI yields opposite chirality XIV. Conversion of XIVto the enantiomerically pure diacid XV is accomplished by treatment withlithium hydroxide/hydrogen peroxide in THF/water, followed by acids suchas trifluoroacetic acid. The compound XV is then converted toenantiomerically pure anhydride III-A by treatment with acetyl chloride.The use of a Friedel-Crafts reaction as in method A then converts II-Ato I-D.

D-2. Biphenyl starting material II may also first be reacted in aFriedel-Crafts reaction as earlier described with succinic anhydridefollowed by Fisher esterification with a lower alcohol such as methanolin the presence of a strong acid such as sulfuric acid to form acylderivative I-D-II. The carbonyl group of this material is then blockedas a ketal such as that formed by treatment with1,2-bistrimethyl-silyloxyethane in the presence of a catalyst such astrimethyl-silyltriflate in a suitable solvent. Many other ketalderivatives and reaction conditions familiar to those skilled in the artcan also be used in this step. Basic hydrolysis of the ester followed byreaction of the resultant I-D-III with XI in the presence of an amidecoupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideyields amide I-D-IV. Reaction of this chiral amide with an alkylatingagent such as alkyl or arylalkyl triflate or halide yieldsenantiomerically enriched product I-D-V which can be converted to finalproduct I-D-VI by treatment with a weak base such as lithiumhydroxide/hydrogen peroxide and then acid. These deblocking steps can beconducted in either order. ##STR30##

General Method E--Compounds in which R⁶ are alkyl- or aryl- orheteroaryl- or acyl- or heteroarylcarbonyl-thiomethylene are prepared bymethods analogous to those described in the patent WO 90/05719. Thussubstituted itaconic anhydride XVI (n=1) is reacted under Friedel-Craftsconditions to yield acid I-E-1 which can be separated by chromatographyor crystallization from small amounts of isomeric analogs of I-E-5.Alternatively, I-E-5 are obtained by reaction of invention compoundsI-E-4 (from any of Methods A through D) with formaldehyde in thepresence of a base.

Compounds I-E-1 or I-E-5 are then reacted with a mercapto derivativeXVII or XVIII in the presence of a catalyst such as Potassium carbonate,ethyldiisobutylamine, tetrabutylammonium fluoride or free radicalinitiators such as azobisisobutyronitrile (AIBN) in a solvent such asdimethylformamide or tetrahydrofuran to yield invention compounds I-E-2,I-E-3, I-E-6 or I-E-7. ##STR31##

General Method F--Reaction of optionally substituted maleic anhydrideXIX under Friedei-Crafts conditions with II yields invention compoundI-F-1, which in turn is reacted with either of mercapto derivatives XVIIor XVIII to yield invention compounds I-F-2 or I-F-3 or with substitutedamine XX to yield invention compounds I-F-4. ##STR32##

General Method G--When they are not commercially available, the succinicanhydrides III-H are prepared via a Stobbe Condensation of a dialkylsuccinate XXI with an aldehyde or ketone XXII to yield unsaturatedhemiester XXIII, followed by catalytic hydrogenation to yield hemiesterXXIV. This intermediate XXIV is then hydrolized to a diacid XXV and thenconverted to the anhydride III-H by reaction with acetyl chloride oracetic anhydride (Method G-1). For a review of the Stobbe condensation,including lists of suitable solvents and bases see W. S. Johnson and G.H. Daub, Org. React., 6, 1 (1951). Method G-1, as applied to thepreparation of III-H (R⁶ =H, R=H, isopropyl and n-butyl), has beendescribed by D. Wolanin, et al., U.S. Pat. No. 4,771,038, Sep. 13, 1988.

Alternatively the hemiester XXIV is converted by treatment with thionylchloride or oxalyl chloride to the acid chloride IV-H (Method G-2).

Both the formation of the anhydride from the diacid and the hemiesteracid chloride from the hemiester acid can be accomplished with severalreagents familiar to those skilled in the art. ##STR33##

General Method H--Biaryl compounds such as those of this application mayalso be prepared by Suzuki or Stille cross-coupling reactions of aryl orheteroaryl metallic compounds in which the metal is zinc, tin,magnesium, lithium, boron, silicon, copper, cadmium or the like with anaryl or heteroaryl halide or triflate (trifluoromethane-sulfonate) orthe like. In the drawing below either Met or X is the metal and theother is the halide or triflate. Pd(com) is a soluble complex ofpalladium such as tetrakis(triphenylphosphine)-palladium(0) orbis-(triphenylphosphine)-palladium(II) chloride. These methods are wellknown to those skilled in the art. See, for example, A. Suzuki, PureAppl. Chem., 66, 213-222 (1994); A. Suzuki, Pure Appl. Chem., 63,419-422 (1991); and V. Farina and G. Roth, "Metal-Organic Chemistry"Volume 5 (Chapter 1), 1994 (in press).

The starting materials XXVII-A are readily formed using methodsanalogous to those of methods A, B or C but using a halobenzene ratherthan a biphenyl as starting material. When desired, the materials inwhich X is halo can be converted to those in which X is metal byreactions well known to those skilled in the art such as treatment of abromo intermediate with hexamethylditin and palladiumtetrakistriphenylphosphine in toluene at reflux to yield thetrimethyltin intermediate. The starting materials XXVII-B are mostconveniently prepared by method C but using readily available heteroarylrather than biphenyl starting materials. The intermediates XXVI-A andXXVI-B are either commercial or easily prepared from commercialmaterials by methods well known to those skilled in the art.

These general methods are useful for the preparation of compounds forwhich Friedel-Crafts reactions such as those of Methods A, B, C, D, E orF would lead to mixtures with various biaryl acylation patterns. MethodH is also especially useful for the preparation of products in which thearyl groups A or B contain one or more heteroatoms (heteroaryls) such asthose compounds that contain thiophene, furan, pyridine, pyrrole,oxazole, thiazole, pyrimidine or pyrazine rings or the like instead ofphenyls (I-H-2, I-H-3 or I-H-4 below). ##STR34##

General Method I--When the R⁶ groups of method F form together a 4-7member carbocyclic ring as in Intermediate XXIX below, the double bondcan be moved out of conjugation with the ketone group by treatment withtwo equivalents of a strong base such as lithium diisopropylamide orlithium hexamethylsilylamide or the like followed by acid quench toyield compounds with the structure XXX. Reaction of XXX with mercaptoderivatives using methods analogous to those of General Method E thenleads to cyclic compounds I-I-1 or I-I-2. ##STR35##

General Method J--Invention compounds in which two R⁶ groups form a 4-7member carbocyclic ring as in I-J below and R¹⁴ is alkyl or arylalkylare prepared according to method J. Starting material XXXI is reactedwith two equivalents of a strong base such as lithium diisopropylamide(LDA) followed by an alkyl or arylalkyl halide (R¹⁴ X) to yieldintermediate XXXII. This material is then reduced to the alcohol with areducing agent capable of selective reduction of the ketone such assodium borohydride, followed by dehydration withtriphenylphosphine/diethyl azodicarboxylate (DEAD) in a suitable solventsuch as THF at reflux to yield XXXIII. Hydrolysis of the ester withaqueous base followed by amide formation with R¹² ONHR¹² (R is loweralkyl but usually CH₃) in the presence of a coupling agent such asdicyclohexyldiimide (DCC) yields XXXIV. Other acyl activating groupswell known to those skilled in the art such as acid chlorides or mixedanhydrides could be used instead of XXXIV. Substituted biphenyl halideXXXV is reacted with an alkyl lithium such as two equivalents of t-butyllithium to yield lithiated biphenyl XXXVI which is then reacted withactivated acyl compound XXXIV. The resultant intermediate XXXVII is thentreated with diethylaluminum cyanide to yield intermediate XXXVIII whichis then hydrolyzed with aqueous acid to yield invention compound I-Jwhich is purified by chromatography on silica gel to afford pureisomers. ##STR36##

General Method K--Invention compounds in which two R6 groups togetherform a pyrrolidine ring are prepared according to method K. Startingmaterial XXXIX (L-pyroglutaminol) is reacted under acid catalysis withbenzaldehyde XXXX (may be substituted) to yield bicyclic derivativeXXXXI. A double bond is then introduced using phenylselenenylmethodology well known to those skilled in the art to yield XXXXII,which, in turn, is reacted with a vinylcopper (I) complex to yieldconjugate addition product XXXXIII. Such reactions in which Lig can be,for example, another equivalent of vinyl group or halide are well knownto those skilled in the art. Hydride reduction (lithium aluminum hydrideor the like) of XXXXIII followed by a standard blocking with, forexample, t-butyldimethylsilylchloride yields XXXXIV which in turn isreacted with an optionally substituted benzylchloroformate XXXXV toyield XXXXVI. Ozonolysis of this intermediate followed by reductiveworkup (dimethylsulfide, zinc/acetic acid or the like) leads to aldehydeXXXXVII. Reaction of this aldehyde with a biphenyl organometallic suchas XXXVI yields alcohol XXXXVIII. Deblocking of the silyl group with,for example, tetrabutylammonium fluoride followed by oxidation with, forexample, pyridiniumdichromate or the like yields claimed compound 1-K-1in which R¹⁴ is a carbobenzyloxy group.

Alternatively the carbobenzyloxy group is removed by reaction withhydrogen and a catalyst such as palladium on carbon to yield theunsubstituted invention compound 1-K-2 optionally followed byN-alkylation to yield compound 1-K-3. These final steps are well knownto those skilled in the art. Alternatively the intermediate XXXXIV canbe directly treated with ozone followed by the other steps of thismethod to yield 1-K-3 in which R¹⁴ is optionally substituted benzylrather than 1-K-1.

This method is especially useful to prepare single enantiomers becausestarting material XXXIX is available as either the isomer as drawn or asD-pyroglutaminol to yield enantiomeric products. ##STR37##

General Method L--The compounds of this invention in which E representsa substituted chain of 3 carbons are prepared by method L. IntermediatesLI, if not available from commercial sources, are prepared by reactionof an activated biphenylcarboxylic acid derivative XXXXIX withsubstituted acetic acid L which has been converted to its bis anion withtwo equivalents of a strong base such as LDA followed by heating todecarboxylate the intermediate keto acid. LI is then treated withmethylenemalonate derivative LII in the presence of a strong base suchas sodium hydride to yield substituted malonate LIII. This malonate canbe further alkylated under conditions familiar to those skilled in theart to yield LIV which in turn is treated with acid and then heated toyield invention compound 1-L-1. Alternatively the final alkylation canbe omitted to yield products in which the R6 adjacent to the carboxyl isH. Alternatively LI can be alkylated with 3-halopropionate ester LV inthe presence of base such as LDA to yield ester 1-L-2 which can then behydrolyzed with aqueous base to yield invention compound 1-L-3 upontreatment with acid. This method is especially useful if any of thegroups R⁶ contain aromatic residues. ##STR38##

Method M--Amides of the acids of the invention compounds can be preparedfrom the acids by treatment in an appropriate solvent such asdichloromethane or dimethylformamide with a primary or secondary amineand a coupling agent such as dicyclohexylcarbodiimide. These reactionsare well known to those skilled in the art. The amine component can besimple alkyl or arylalkyl substituted or can be amino acid derivativesin which the carboxyl is blocked and the amino group is free.

The compounds of the present invention have been found to inhibit thematrix metalloproteases MMP-3, MMP-9 and MMP-2, and to a lesser extentMMP-1, and are therefore useful for treating or preventing theconditions referred to in the background section. As other MMPs notlisted above share a high degree of homology with those listed above,especially in the catalytic site, it is deemed that compounds of theinvention should also inhibit such other MMPs to varying degrees.Varying the substituents on the biaryl portions of the molecules, aswell as those of the propanoic or butanoic acid chains of the claimedcompounds, has been demonstrated to affect the relative inhibition ofthe listed MMPs. Thus compounds of this general class can be "tuned" byselecting specific substituents such that inhibition of specific MMP(s)associated with specific pathological conditions can be enhanced whileleaving non-involved MMPs less affected.

The method of treating matrix metalloprotease-mediated conditions may bepracticed in mammals, including humans, which exhibit such conditions.

The inhibitors of the present invention are contemplated for use inveterinary and human applications. For such purposes, they will beemployed in pharmaceutical compositions containing active ingredient(s)plus one or more pharmaceutically acceptable carriers, diluents,fillers, binders, and other excipients, depending on the administrationmode and dosage form contemplated.

Administration of the inhibitors may be by any suitable mode known tothose skilled in the art. Examples of suitable parenteral administrationinclude intravenous, intraarticular, subcutaneous and intramuscularroutes. Intravenous administration can be used to obtain acuteregulation of peak plasma concentrations of the drug. Improved half-lifeand targeting of the drug to the joint cavities may be aided byentrapment of the drug in liposomes. It may be possible to improve theselectivity of liposomal targeting to the joint cavities byincorporation of ligands into the outside of the liposomes that bind tosynovial-specific macromolecules. Alternatively intramuscular,intraarticular or subcutaneous depot injection with or withoutencapsulation of the drug into degradable microspheres e.g., comprisingpoly(DL-lactide-co-glycolide) may be used to obtain prolonged sustaineddrug release. For improved convenience of the dosage form it may bepossible to use an i.p. implanted reservoir and septum such as thePercuseal system available from Pharmacia. Improved convenience andpatient compliance may also be achieved by the use of either injectorpens (e.g. the Novo Pin or Q-pen) or needle-free jet injectors (e.g.from Bioject, Mediject or Becton Dickinson). Prolonged zero-order orother precisely controlled release such as pulsatile release can also beachieved as needed using implantable pumps with delivery of the drugthrough a cannula into the synovial spaces. Examples include thesubcutaneously implanted osmotic pumps available from ALZA, such as theALZET osmotic pump.

Nasal delivery may be achieved by incorporation of the drug intobioadhesive particulate carriers (<200 μm) such as those comprisingcellulose, polyacrylate or polycarbophil, in conjunction with suitableabsorption enhancers such as phospholipids or acylcarnitines. Availablesystems include those developed by DanBiosys and Scios Nova.

Oral delivery may be achieved by incorporation of the drug into tablets,coated tablets, dragees, hard and soft gelatine capsules, solutions,emulsions or suspensions. Oral delivery may also be achieved byincorporation of the drug into enteric coated capsules designed torelease the drug into the colon where digestive protease activity islow. Examples include the OROS-CT/Osmet™ and PULSINCAP™ systems fromALZA and Scherer Drug Delivery Systems respectively. Other systems useazo-crosslinked polymers that are degraded by colon specific bacterialazoreductases, or pH sensitive polyacrylate polymers that are activatedby the rise in pH at the colon. The above systems may be used inconjunction with a wide range of available absorption enhancers.

Rectal delivery may be achieved by incorporation of the drug intosuppositories.

The compounds of this invention can be manufactured into the abovelisted formulations by the addition of various therapeutically inert,inorganic or organic carriers well known to those skilled in the art.Examples of these include, but are not limited to, lactose, corn starchor derivatives thereof, talc, vegetable oils, waxes, fats, polyols suchas polyethylene glycol, water, saccharose, alcohols, glycerin and thelike. Various preservatives, emulsifiers, dispersants, flavorants,wetting agents, antioxidants, sweeteners, colorants, stabilizers, salts,buffers and the like are also added, as required to assist in thestabilization of the formulation or to assist in increasingbioavailability of the active ingredient(s) or to yield a formulation ofacceptable flavor or odor in the case of oral dosing.

The amount of the pharmaceutical composition to be employed will dependon the recipient and the condition being treated. The requisite amountmay be determined without undue experimentation by protocols known tothose skilled in the art. Alternatively, the requisite amount may becalculated, based on a determination of the amount of target enzymewhich must be inhibited in order to treat the condition.

The matrix metalloprotease inhibitors of the invention are useful notonly for treatment of the physiological conditions discussed above, butare also useful in such activities as purification of metalloproteasesand testing for matrix metalloprotease activity. Such activity testingcan be both in vitro using natural or synthetic enzyme preparations orin vivo using, for example, animal models in which abnormal destructiveenzyme levels are found spontaneously (use of genetically mutated ortransgenic animals) or are induced by administration of exogenous agentsor by surgery which disrupts joint stability.

Experimental

General Procedures:

All reactions were performed in flame-dried or oven-dried glasswareunder a positive pressure of argon and were stirred magnetically unlessotherwise indicated. Sensitive liquids and solutions were transferredvia syringe or cannula and were introduced into reaction vessels throughrubber septa. Reaction product solutions were concentrated using a Buchievaporator unless otherwise indicated.

Materials:

Commercial grade reagents and solvents were used without furtherpurification except that diethyl ether and tetrahydrofuran were usuallydistilled under argon from benzophenone ketyl, and methylene chloridewas distilled under argon from calcium hydride. Many of the specialtyorganic or organometallic starting materials and reagents were obtainedfrom Aldrich, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233.Solvents are often obtained from EM Science as distributed by VWRScientific.

Chromatography:

Analytical thin-layer chromatography (TLC) was performed on Whatman®pre-coated glass-backed silica gel 60 A F-254 250 μm plates.Visualization of spots was effected by one of the following techniques:(a) ultraviolet illumination, (b) exposure to iodine vapor, (c)immersion of the plate in a 10% solution of phosphomolybdic acid inethanol followed by heating, and (d) immersion of the plate in a 3%solution of p-anisaldehyde in ethanol containing 0.5% concentratedsulfuric acid followed by heating.

Column chromatography was performed using 230-400 mesh EM Science®silica gel.

Analytical high performance liquid chromatography (HPLC) was performedat 1 mL min⁻¹ on a 4.6×250 mm Microsorb® column monitored at 288 nm, andsemi-preparative HPLC was performed at 24 mL min⁻¹ on a 21.4×250 mmMicrosorb® column monitored at 288 nm.

Instrumentation:

Melting points (mp) were determined with a Thomas-Hoover melting pointapparatus and are uncorrected.

Proton (¹ H) nuclear magnetic resonance (NMR) spectra were measured witha General Electric GN-OMEGA 300 (300 MHz) spectrometer, and carbonthirteen (¹³ C) NMR spectra were measured with a General ElectricGN-OMEGA 300 (75 MHz) spectrometer.

Mass spectral (MS) data were obtained on a Kratos Concept 1-Hspectrometer by liquid-cesium secondary ion (LCIMS), an updated versionof fast atom bombardment (FAB). ##STR39##

EXAMPLE 1, EXAMPLE 2, EXAMPLE 3, EXAMPLE 4, EXAMPLE 5, AND EXAMPLE 6(Reference with respect to composition):

4-Chlorobiphenyl (2.859 g, 15.154 mmoles, supplied by TCI) was weighedinto a 500 mL flask which had been purged with argon. Into this flaskwas transferred dihydro-3-(2-methylpropyl)-2,5-furandione (1.997g,15.110 mmoles, for preparation see below) with1,1,2,2-tetachloroethane (50 mL). The solution was cooled in an ice bathand then aluminum trichloride (4.09 g) was slowly added as a solid. Theice bath was removed and the reaction was allowed to warm to roomtemperature. The mixture was then heated in an oil bath for a total of2.5 hours at which time the reaction was cooled in an ice bath andquenched with 10% HCL solution (200 mL). The aqueous mixture wasextracted thrice with ethyl acetate and the combined organic extractswashed once with brine. The solution was dried over MgSO₄ andconcentrated in vacuuo. Purification by flash chromatography(hexane-ethyl acetate) provided an oil that was recrystallized twice(hexane-ethyl acetate) to provide 1.358 g of a light orange solid whichwas mostly one material. Chromatography (ethyl acetate-hexane) of asmall amount of this material yielded 52.0 mg of Example 1(mp=138.5°-139.5° C.) as a white fluffy solid and 4.0 mg of Example 6(mp=185.5°-186.5° C.) as side product from succinic anhydride as a minorimpurity of dihydro-3-(2-methylpropyl)-2,5-furandione.

The mother liquors from a similarly prepared batch of Example 1 wereevaporated in vacuo and the residue evaluated by NMR spectroscopy toshow the presence of an isomer, 5-methyl-3-oxo-(4'-chloro-4-biphenyl)methyl!hexanoic acid, as a significantcomponent. This residue was prepurified by flash silica chromatography(methylene chloride-methanol) to remove extraneous contaminants and thenseparated on a Chiralpak AD® HPLC column (65% n-heptane, 35% (1%water+0.2% TFA in ethanol)) to yield enantiomers of the regioisomer(Example 4/Example 5 mixed) along with those of Example 1. Separation ofpure Example 1 on the same system yielded only the isomers of thiscompound as Example 2 (first off) and Example 3 (second off).Re-chromatography of the regioisomer mixture on a Chiralcel OJ® columngave pure samples of Example 5 (first off) and Example 4 (second off).

In a separate experiment run in a similar manner using pure succinicanhydride instead of the above anhydride, the only product was Example6.

EXAMPLE 1

TLC (methylene chloride-2.5% methanol) Rf=0.20; ¹ H NMR (DMSO-d₆) δ12.12 (s, 0.6 H), 8.03 (d, J=8.43 Hz, 2 H), 7.80 (d, J=8.43 Hz, 2 H),7.76 (d, J=8.43 Hz, 2 H), 7.53 (d, J=8.43 Hz, 2 H), 3.59 (d, J=9.16 Hz ,d 3.30 solvent), 3.10 (dd, J=18.15 Hz, J=4.22 Hz, 1 H), 2.85 (M, 1H),1.65 (m, 1 H), 1.50 (m, 1H), 1.33 (m, 1H), 0.88 (d, J=6.6 Hz, 3H), 0.78(d, J=6.6 Hz, 3H); ¹³ C NMR (DMSO-d6) δ 199.13, 177.13, 144.2, 138.74,136.59, 134.42, 130.15, 129.87, 129.77, 127.94, 41.96, 41.50, 39.27,26.38, 23.53, 23.43; IR (soln) 1706.7, 1687.4, 1606.4 cm⁻¹ ; MS(FAB-LSIMS) 345 M+H!⁺ (C₂₀ H₂₁ O₃ Cl, FW=344.84); Anal. C: calcd, 69.66;found, 69.73. H: calcd, 6.14; found, 6.20. Cl: calcd, 10.28, found,10.35.

EXAMPLE 2

A! D=-26.3 (MEOH), >99.8% ee by chiral HPLC, ¹ H NMR identical toExample 1.

EXAMPLE 3

A! D=+25.4 (MEOH), >99.8% ee by chiral HPLC, ¹ H NMR identical toExample 1.

EXAMPLE 4

α!D -26.3 (MeOH); >99% ee by chiral HPLC; ¹ H NMR (CDCl₃) δ 8.05 (d, J=8Hz, 2H), 7.66 (d, J=8 Hz, 2H), 7.56 (d, J=8 Hz, 2H), 7.45 (d, J=8 Hz,2H), 3.9 (m, 1H), 2.98 (dd, J=9 Hz, J=17 Hz, 1H), 2.58 (dd, J=4 Hz, J=17Hz, 1H), 1.3-1.7 (m, 3H), 1.01 (d, J=6 Hz, 3H), 0.87 (d, J=6 Hz, 3H); ¹³C NMR (CDCl₃) δ 203.09, 177.28, 145.19, 138.94, 135.87, 135.13, 129.82,129.17, 127.88, 42.09, 40.86, 35.84, 26.52, 23.77, 22.61; MS (FAB-LSIMS)345 M+H!⁺ (C₂₀ H₂₁ O₃ Cl, FW=344.84).

EXAMPLE 5

α!D +26.1 (MeOH); >99% ee by chiral HPLC; ¹ H NMR, ¹³ C NMR and MSidentical to Example 4. ##STR40##Dihydro-3-(2-methylpropl)-2,5-furandione:

This intermediate was prepared according to the general procedures givenin Wolanin, et al., U.S. Pat. No. 4,771,038 (Sept. 13, 1988--Examples 6and 5c). The ¹ H NMR spectra of the intermediates and final productmatched those given in the experimental procedures of that patent.

Example 1--Later Preparations and General Procedure.

4-Chlorobiphenyl (14.8 mmoles, 1 EQ) was weighed into a 250 mL flaskwhich had been purged with argon. Into this flask was transferreddihydro-3-(2-methylpropyl)-2,5-furandione (14.9 mmoles, 1 EQ) with1,1,2,2-tetachloroethane (50 mL). The solution was cooled in an ice bathand then aluminum trichloride (30.8 mmoles, 2.07 EQ) was slowly added asa solid. The ice bath was removed after approximately 30 minutes and thereaction was allowed to warm to room temperature and allowed to stir forat least 24 hours. It was then poured into cold 10% HCL solution andextracted three to five times with chloroform. The combined organicextracts washed once with brine, dried over MgSO₄ and concentrated invacuo. Purification by flash chromatography (methylenechloride-methanol) provided an oil that was recrystallized twice(hexane-ethyl acetate) to provide 1.066 grams of white solid (Example1). The mother liquors from recrystallization were a mixture ofregioisomers and a small amount of Example 6.

The above general method was used to prepare the following series ofsubstituted biphenyl products using either the substituted anhydridedihydro-3-(2-methylpropyl)-2,5-furandione or succinic anhydride alongwith the indicated substituted biphenyls:

From Succinic Anhydride: Example 6, Example 7, Example 8, Example 9,Example 10, Example 11, Example 12.

From Dihydro-3-(2-methylpropyl)-2,5-furandione: Example 13, Example 14,Example 15, Example 16, Example 17, Example 18, Example 19, Example 20,Example 21, Example 22, Example 23.

EXAMPLE 6

From 4-chlorobiphenyl and pure succinic anhydride: TLC (methylenechloride-2.5% methanol) R_(f) =0.09; ¹ H NMR (DMSO-d₆) δ 8.04 (d, J=8.43Hz, 2H), 7.81 (d, J=8.43 Hz, 2H), 7.76 (d, J=8.43 Hz, 2 H), 7.53 (d,J=8.43 Hz, 2 H), 3.26 (t, J=6.23 Hz, 2H), 2.56 (t, J=6.23 Hz, 2H); ¹³ CNMR (DMSO-d₆) δ 199.13, 174.97, 144.24, 138.79, 136.60, 134.43, 130.17,129.89, 129.75, 128.00, 34.25, 28.97; MS (FAB-LSIMS) 289 M+H!⁺ (C₁₆ H₁₃O₃ Cl, FW=288.73); Anal. C: calcd, 66.56; found, 66.46. H: calcd, 4.54;found, 4.45. ##STR41##

EXAMPLE 7 (Reference with respect to composition)

From 4-bromobiphenyl: MP 201.5°-202.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.11; ¹ H NMR (DMSO-d₆) δ 8.03 (d, J=8.46 Hz, 2H), 7.80(d, J=8.46 Hz, 2 H), 7.67 (m, 4H), 3.25 (t, J=6.25 Hz, 2H), 2.58 (t,J=6.25 Hz, 2H); ¹³ C NMR (DMSO-d₆) δ 199.11, 174.94, 144.27, 139.13,136.61, 133.08, 130.15, 129.73, 127.92, 123.08, 34.26, 28.96; MS(FAB-LSIMS) 333 M+H!⁺ (C₁₆ H₁₃ O₃ Br, FW=333.18); Anal. C: calcd, 57.68;found, 57.41. H: calcd, 3.93; found, 4.00. ##STR42##

EXAMPLE 8 (Reference with respect to composition)

From 4-fluorobiphenyl: MP 176.0°-177.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.10; ¹ H NMR (DMSO-d₆) δ 12.13 (S, 1H), 8.03 (d,J=8.42 Hz, 2H), 7.79 (m, 4H), 7.31 (t, J=9.02 Hz, 2H), 3.26 (t, J=6.16Hz, 2H), 2.57 (t, J=6.01 Hz, 2H); ¹³ C NMR (DMSO-d₆) δ 199.10, 174.95,165.13, 161.86, 144.53, 136.47, 136.42, 136.29, 130.24,130.14, 129.68,127.92, 117.17, 116.89, 32.22, 28.97; MS (FAB-LSIMS) 273 M+H!⁺ (C₁₆ H₁₃O₃ F, FW=272.28); Anal. C: calcd, 70.58; found, 70.62. H: calcd, 4.81;found, 4.73. ##STR43##

EXAMPLE 9 (Reference with respect to composition)

From 2-fluorobiphenyl: MP 158.0°-159.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.10; ¹ H NMR (DMSO-d₆) δ 12.15 (s, 1H), 8.06 (d,J=8.42 Hz, 2 H), 7.69 (dd, J=1.5 Hz, J=8.42 Hz, 2H), 7.58 (m, 1H), 7.46(m, 1H), 7.33 (m, 2H), 3.27 (t, J=6.31 Hz, 2 H), 2.58 (t, J=6.31 Hz, 2H); ¹³ C NMR (DMSO-d₆) δ 199.23, 174.9, 161.81, 158.54, 140.73, 136.66,131.91, 131.88, 131.59, 131.48, 130.23, 130.20, 129.27, 128.36, 128.18,126.23, 126.18, 117.51, 117.22, 34.26, 28.96; MS (FAB-LSIMS) 273 M+H!⁺(C₁₆ H₁₃ O₃ F, FW=272.28); Anal. C: calcd, 70.58; found, 70.47. H:calcd, 4.81; found, 4.89. ##STR44##

EXAMPLE 10 (Reference with respect to composition)

From 2-chlorobiphenyl: MP 175.0°-176.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.09; ¹ H NMR (DMSO-d₆) δ 12.16 (s, 1 H), 8.09 (d,J=8.12 Hz, 2H), 7.57, 7.39 (m, 6H), 3.27 (t, J=6.30 Hz, 2H), 2.59 (t,J=6.30 Hz, 2H); ¹³ C NMR (DMSO-d₆) δ 99.24, 174.94, 144.37, 139.92,136.68, 132.46, 132.24, 131.06, 130.91, 130.75, 128.91, 128.75, 34.24,28.98; MS (FAB-LSIMS) 289 M+H!⁺ (C₁₆ H₁₃ O₃ Cl, FW=288.73); Anal. C:calcd, 66.56; found, 66.17. H: calcd, 4.54; found, 4.57. ##STR45##

EXAMPLE 11 (Reference with respect to composition)

From 2,4-difluorobiphenyl: MP 133.0°-134.0° C.; TLC (methylenechloride-2.5% methanol) R_(f) =0.09; ¹ H NMR (DMSO-d₆) δ 12.15 (s,1 H),8.05 (d, J=8.42 Hz, 2H), 7.65, 7.40, 7.22 (m, 6H), 3.27 (t, J=6.31 Hz,2H), 2.58 (t, J=6.0 Hz, 2H); ¹³ C NMR (DMSO-d₆) δ 199.17, 174.94,165.00, 164.84, 162.02, 161.86, 161.73, 161.56, 158.72, 158.56, 139.89,136.68, 133.22, 133.16, 133.09, 133.03, 130.19, 130.15, 129.30, 125.03,124.98, 124.87, 124.81, 120.25, 113.54, 113.50, 113.26, 113.21, 106.15,105.80, 105.44, 34.24, 28.94; MS (FAB-LSIMS) 291 M+H!⁺ (C₁₆ H₁₂ O₃ F₂,FW=290.27); Anal. C: calcd, 66.21; found, 65.97. H: calcd, 4.17; found,4.00. ##STR46##

EXAMPLE 12 (Reference with respect to composition)

From 3-chlorobiphenyl: MP 147.0°-148.0° C.; ¹ H NMR (DMSO-d₆) δ 12.3(bs,1 H), 8.03 (d, J=8 Hz, 2H), 7.4-7.9 (m, 6H), 3.25 (t, J=3 Hz, 2H),2.60 (t, J=3 Hz, 2H); ¹³ C NMR (DMSO-d₆) δ 198.0, 173.9, 142.9, 141.0,135.7, 133.9, 130.9, 128.2, 128.2, 127.1, 126.7, 125.7, 33.2, 27.9; MS(FAB-LSIMS) 289 M+H!⁺ (C₁₆ H₁₃ O₃ Cl, FW=290.27); Anal. C: calcd, 66.56;found, 65.9. H: calcd, 4.54; found, 4.56. ##STR47##

EXAMPLE 13

From biphenyl: MP 134.5°-135.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.19; ¹ H NMR (DMSO-d₆) δ 12.13 (s, 0.7H), 8.03 (d,J=8.43 Hz, 2H), 7.79 (d, J=8.43 Hz, 2H), 7.72 (d, J=8.43 Hz, 2H), 7.44(d, J=8.43 Hz, 2H), 3.35 (dd, J=18.14 Hz, J=10.2 Hz, 1 H), 3.09 (dd,J=17.96 Hz, J=4.4 Hz, 1H), 1.65 (m, 1H), 1.50 (m, 1H), 1.33 (m, 1H),0.92 (d, J=6.6 Hz, 3H), 0.82 (d, J=6.6 Hz, 3H); ¹³ C NMR (DMSO-d₆) δ199.18, 177.77, 145.66, 139.99, 136.36, 130.20, 129.75, 129.50, 128.10,128.00, 41.99, 41.50, 39.31, 26.40, 23.56, 23.45; MS (FAB-LSIMS) 311M+H!⁺ (C₂₀ H₂₂ O₃, FW=310.38); Anal. C: calcd, 77.39; found, 77.25. H:calcd, 7.14; found, 7.12. ##STR48##

EXAMPLE 14

From 4-bromobiphenyl: MP 149.0°-150.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.16; ¹ H NMR (DMSO-d₆) δ 8.05 (d, J=10 Hz, 2H), 7.66(m, 4H), 7.50 (d, J=10 Hz, 2H), 3.46 (dd, J=18 Hz, J=6 Hz, 1H), 3.12 (m,2H), 1.72 (m, 2H), 1.42 (m, 1H), 1.02 (d, J=6 Hz, 3H), 0.90 (d, J=6 Hz,3H); ¹³ C NMR (DMSO-d₆) δ 198.22, 182.93, 151.79, 145.25, 139.36,136.16, 132.78, 129.49, 129.45, 127.72, 123.37, 41.79, 41.30, 39.11,26.55, 23.20, 23.03; MS (FAB-LSIMS) 389 M+H!⁺ (C₂₀ H₂₁ O₃ Br,FW=389.28); Anal. C: calcd, 61.71; found, 61.88. H: calcd, 5.44; found,5.40. ##STR49##

EXAMPLE 15

From 4-fluorobiphenyl: MP 117.5°-118.5° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.16; ¹ H NMR (DMSO-d₆) δ 8.04 (d, J=8.46 Hz, 2H), 7.61(m, 4H), 7.16 (t, J=8.64 Hz, 2H), 3.47 (dd, J=17.29 Hz, J=8.45 Hz, 1H),3.12 (m, 2H), 1.72 (m, 2H), 1.44 (m, 1H), 1.01 (d, J=6 Hz, 3H), 0.91 (d,J=6 Hz, 3H); ¹³ C NMR (DMSO-d₆) δ 198.22, 182.72, 165.30, 162.02,145.53, 136.63, 136.58, 135.85, 129.65, 129.54, 129.38, 127.75, 116.72,116.43, 41.78, 41.27, 39.07, 26.54, 23.20, 22.98; MS (FAB-LSIMS) 329M+H!⁺ (C₂₀ H₂₁ O₃ F, FW=328.39); Anal. C: calcd, 73.15; found, 73.30. H:calcd, 6.45; found, 6.43. ##STR50##

EXAMPLE 16

From 4-ethylbiphenyl: MP 153.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.16; ¹ H NMR (DMSO-d₆) δ 12.2 (s, 0.8H), 8.02 (d, J=8Hz, 2H), 7.78 (d, J=8 Hz, 2H), 7.63 (d, J=8 Hz, 2 H), 7.30 (d, J=8 Hz,2H), 3.34 (dd- solvent), 3.08 (dd, J=18 Hz, J=6 Hz, 1H), 2.76 (m, 1H),2.60 (q, J=18 Hz, J=6 Hz, 2H), 1.64 (m, 1H), 1.48 (m, 1H), 1.32 (m, 1H),1.18 (t, J=6 Hz, 3H), 0.91 (d,J=6 Hz, 3H), 0.81 (d, J=6 Hz, 3H); ¹³ CNMR (DMSO-d₆) δ 199.12, 177.77, 145.64, 145.30, 137.35, 136.09, 129.73,129.63, 128.02, 127.69, 41.99, 41.46, 39.29, 28.95, 26.40, 23.56, 23.43,16.63; MS (FAB-LSIMS) 339 M+H!⁺ (C₂₂ H₂₆ O₃, FW=338.45); Anal. C: calcd,78.08; found, 77.74. H: calcd, 7.74; found, 7.72. ##STR51##

EXAMPLE 17

From 2-fluorobiphenyl: MP 119.0°-120.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.12; ¹ H NMR (DMSO-d₆) δ 12.18 (s, 0.7 H), 8.09 (d,J=13 Hz, 2H), 7.96 (d, J=13 Hz, 2 H), 7.78, 7.65, 7.44, (m, 4H), 3.35(dd, J=17 Hz, J+10 Hz, 1H), 3.10 (dd, J=17 Hz, J=4 Hz, 1H), 2.85 (m,1H), 1.64 (m, 1H), 1.50 (m, 1H), 1.32 (m, 1H), 0.91 (d, J=6 Hz, 3H),0.81 (d, J=6 Hz, 3H); ¹³ C NMR (DMSO-d₆) δ 199.23, 177.74, 161.83,158.57, 140.78, 136.68, 131.92, 131.88, 131.59, 131.49, 130.22, 130.19,129.32, 128.36, 128.20, 126.24, 126.19, 117.51, 117.22, 41.97, 41.51,39.29, 26.40, 23.53, 23.43; MS (FAB-LSIMS) 329 M+H!⁺ (C₂₀ H₂₁ O₃ F,FW=328.39); Anal. C: calcd, 73.15; found, 73.02. H: calcd, 6.45; found,6.48. ##STR52##

EXAMPLE 18

From 2-chlorobiphenyl: MP 118.0°-119.0° C.; TLC (methylene chloride-2.5%methanol) R_(f) =0.18; ¹ H NMR (DMSO-d₆) δ 8.05 (d, J=8.42 Hz, 2H), 7.56(d, J=8.72 Hz, 2H), 7.50, 7.34 (m, 4H), 3.48 (dd, J=8.0 Hz, J=15 Hz,1H), 3.20 (m, 2H), 1.72 (m, 2H), 1.45 (m, 1H), 1.02 (d, 1.02, J=6 Hz,3H), 0.92 (d, J=6 Hz, 3H); ¹³ C NMR (DMSO-d₆) δ 198.31, 182.54, 144.96,140.02, 136.18, 132.96, 131.17, 130.78, 130.46, 129.90, 128.54, 127.67,41.77, 41.31, 38.97, 26.54, 23.18, 23.02; MS (FAB-LSIMS) 345 M+H!⁺ (C₂₀H₂₁ O₃ F, FW=328.37); Anal. C: calcd, 69.66; found, 69.41. H: calcd,6.14; found, 6.10. Cl: calcd, 10.28 found, 10.24. ##STR53##

EXAMPLE 19

From 4-methoxybiphenyl: MP 141.0°-142.0° C.; TLC (methylenechloride-2.5% methanol) R_(f) =0.21; ¹ H NMR (DMSO-d₆) δ 8.02 (d, J=8.42Hz, 2H), 7.65 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.72 Hz, 2H), 7.01 (d,J=9.02 Hz, 2H), 3.87 (s, 3H) 3.46 (dd, J=15.0 Hz, J=8.0 Hz, 1H), 3.15(m, 2H), 1.72 (m, 2H), 1.44 (m, 1H), 1.02 (d, J=6 Hz, 3H), 0.92 (d, J=6Hz, 3H); ¹³ C NMR (DMSO-d₆) δ 198.24, 182.64, 160.58, 146.74, 135.29,132.87, 128.36, 129.04, 127.30, 115.07, 56.04, 41.80, 41.25, 39.08,26.55, 23.21, 22.98; MS (FAB-LSIMS) 341 M+H!⁺ (C₂₁ H₂₄ O₄, FW=340.42);Anal. C: calcd, 74.09; found, 73.98. H: calcd, 7.11; found, 7.09.##STR54##

EXAMPLE 20

From 2,4-difluorobiphenyl: MP 133.0°-134.0° C.; TLC (methylenechloride-2.5% methanol) R_(f) =0.17; ¹ H NMR (DMSO-d₆) δ 12.17 (s,0.8H), 8.05 (d, J=7.7 Hz, 2H), 7.65, 7.40, 7.22 (m, 6H), 3.34 (m, 1H andsolvent), 3.11 (dd, J=18.02 Hz, J=4.04 Hz, 1H), 0.93 (d, J=6 Hz, 3H),0.83 (d, J=6 Hz, 3H); ¹³ C NMR (DMSO-d₆) δ 199.19, 177.73, 165.00,164.84, 162.02, 161.86, 161.73, 161.56, 158.72, 158.54, 139.91, 136.69,133.21, 133.16, 133.08, 133.03, 130.15, 130.12, 129.33, 125.02, 124.97,124.86, 124.81, 113.52, 113.49, 113.24, 113.20, 106.14, 105.78, 105.43,41.96, 41.49, 39.27, 26.38, 23.50, 23.40; MS (FAB-LSIMS) 347 M+H!⁺ (C₂₀H₂₀ O₃ F₂ FW=346.38). ##STR55##

EXAMPLE 21

From 4-methylbiphenyl: MP 131.5°-132.5° C.; TLC (methylene chloride-2.5%methanol) R_(f) =1.4; ¹ H NMR (CDCl₃) δ 8.03 (d, J=8.4 Hz, 2H), 7.67 (d,J=8.7 Hz, 2H), 7.54(d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 3.46 (m,1H), 3.14 (m,2H), 2.42 (s, 3H), 1.73 (m, 2H), 1.43 (m, 1H), 0.99 (d,J=6.0 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H); ¹³ C NMR (CDCl₃) δ 198.29,182.59, 146.55, 138.92, 137.58, 135.61, 130.35, 129.31, 127.76, 127.65,41.80, 41.27, 39.07, 26.55, 23.21, 22.98, 21.34; MS (FAB-LSIMS) 325M+H!⁺ (C₂₁ H₂₄ O₃ FW=324.42); Anal. C: calcd, 77.75; found, 77.51. H:calcd, 7.46; found, 7.40. ##STR56##

EXAMPLE 22 (Reference)

From 4-chlorobenzene: MP 123.5°-124.5° C.; ¹ H NMR (CDCl₃) δ 7.67 (d,J=9 Hz, 2H), 7.20 (d, J=8 Hz, 2H), 3.15 (dd, J=9 Hz, J=17 Hz,1H), 3.15(dd, J=9 Hz, J=17 Hz, 1H), 2.83 (m, 2H), 1.45 (m, 2H), 1.16 (m, 1H),0.76 (d, J=6 Hz, 3H), 0.66 (d, J=6 Hz, 3H); ¹³ C NMR (CDCl₃) δ 197.53,182.72, 140.39, 135.46, 130.13, 129.60, 41.73, 41.15, 39.02, 26.50,23.13, 22.98; MS (FAB-LSIMS) 269 M+H!⁺ (C₁₄ H₁₇ O₃ Cl FW=268.74); Anal.C: calcd, 62.57; found, 62.50. H: calcd, 6.38; found, 6.39; Cl: calcd,13.19; found, 13.18. ##STR57##

EXAMPLE 23

From 4-pentylbiphenyl: MP 101.0°-102.0° C.; ¹ H NMR (CDCl₃) δ 8.03 (d,J=8 Hz, 2H), 7.678 (d, J=8 Hz, 2H), 7.56 (d, J=8 Hz, 2H), 7.29 (d, J=8Hz, 2H), 3.46 (dd, 1H), 3.10 (m,2H), 2.67 (tr, J=7 Hz, 2H), 1.2-1.8 (m,9H), 0.8-1.0 (m, 9H); ¹³ C NMR (CDCl₃) δ 198.27, 182.54, 146.58, 143.99,137.76, 135.57, 129.70, 129.31, 127.78, 127.67, 41.80, 41.27, 39.05,36.27, 32.17, 31.80, 26.55, 23.21, 22.98, 14.70; MS (FAB-LSIMS) 381M+H!⁺ (C₂₅ H₃₂ O₃ FW=324.42); Anal. C: calcd, 78.91; found, 78.85. H:calcd, 8.48; found, 8.46. ##STR58##

EXAMPLE 24

Example 19 (52.2 mg, 0.153 mmol) was dissolved in 2.5 ml glacial aceticacid and 1.5 ml conc. HBr. This mixture was stirred overnight at ambienttemperature and then refluxed for 13 hours. The reaction was allowed tocool before water was added to precipitate crude solid. This wasdissolved in ethyl acetate and washed with brine. The solution was driedover MgSO₄ and concentrated in vacuo to give a solid that recrystallizedfrom hexane-ethyl acetate as 24.6 mg white crystals.

MP 188.0°-189.0° C.; TLC (methylene chloride--2.5% methanol) R_(f)=0.07; ¹ H NMR (DMSO-d₆) δ 8.02 (d, J=8.42 Hz, 2H), 7.65 (d, J=8.42 Hz,2H), 7.59 (d, J=8.72 Hz, 2H), 7.01 (d, J=9.02 Hz, 2H), 3.87 (s, 3H) 3.46(dd, J=15.0 Hz, J=8.0 Hz, 1H), 3.15 (m, 2H), 1.72 (m, 2H), 1.44 (m, 1H),1.02 (d, J=6 Hz, 3H), 0.92 (d, J=6 Hz, 3H); ¹³ C NMR (DMSO-d₆) δ 198.98,177.76, 159.13, 145.69, 135.35, 130.53, 129.72, 129.30, 126.97, 116.99,26.39, 23.56, 23.44; MS (FAB-LSIMS) 327 M+H!⁺ (C₂₀ H₂₂ O₄, FW=326.40);Anal. C: calcd, 73.60; found, 73.19. H: calcd, 6.76; found, 6.76.##STR59##

EXAMPLE 25 (Reference with respect to composition)

Example 6 (127.2 mg, 0.441 mmole) was dissolved in 2 ml of pyridine. Tothis solution was added 32 mg of paraformaldehyde and 0.5 ml ofpiperidine. The mixture was heated in an oil bath at 55°-60° C. for 6hours, then allowed to stir at ambient temperature overnight. Thereaction was poured into 10% HCl and extracted with EtOAc, washed withsaturated brine, dried over MgSO₄, filtered and solvent was removed invacuo to give a crude solid. This solid was dissolved in EtOAc andfiltered through a cotton plug to remove insoluble material. The residuewas recrystallized with Hexane-EtOAc to give 54.4 mg (41%) whitecrystals.

MP 127.0°-128.0° C.; TLC (methylene chloride-2.5% methanol) R_(f) =0.05;¹ H NMR (CDCl₃) δ 7.88 (d, J=9 Hz, 2H), 7.63 (d, J=9 Hz, 2 H), 7.55 (d,J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H), 6.07 (s, 1H), 5.2 (solvent), 5.87 (s,1H), 3.60 (s, 2H); ¹³ C NMR (CDCl₃) δ 197.27, 176.70, 144.72, 141.15,139.00, 135.52, 135.06, 131.15, 130.28, 129.80, 129.17, 127.47, 38.70;MS (FAB-LSIMS) 301 M+H!⁺ (C₁₇ H₁₃ O₃ Cl, FW=300.74); Anal. C: calcd,67.89; found, 67.64. H: calcd, 4.36; found, 4.31. ##STR60##

EXAMPLE 26 AND EXAMPLE 27

Example 1 (103.5 mg, 0.300 mmole) was dissolved in 20 ml of water withthe addition of 30.0 mg (0.687 mmole) of sodium hydroxide. The solutionwas cooled in an ice bath and then 13.0 mg (0.344 mmoles) of sodiumborohydride was added as a solid. Stirring continued for 1 hour. TLC(methylene chloride-2.5% methanol) indicated that starting material wasstill present, so the reaction was allowed to warm to room temperatureovernight (16.5 hrs). Starting material was still present, so 13.0 mgmore sodium borohydride was added at room temperature. The reaction wasstirred for 2 hours and then quenched with 10% HCl and extracted twicewith ethyl acetate. The combined organic extracts were washed once withbrine and dried over MgSO₄. The solution was concentrated in vacuo togive 57.0 mg of a crude solid. This was purified by silica gelchromatography (methylene chloride-methanol) to give two major productsExample 26 (7.9 mg) and Example 27 (19.1 mg).

EXAMPLE 26

¹ H NMR (MeOD-d₃) δ 7.56 (m, 4H), 7.38 (m, 4H), 4.66 (dd, J=9 Hz, J=3Hz, 1H), 2.77 (m, 1H),1.95 (m, 1H), 1.75, 1.57 (m, 3H), 1.26 (m, 1H),0.85 (d, J=6 Hz, 3H), 0.79 (d, J=6 Hz, 3H).

EXAMPLE 27

¹ H NMR (MeOD-d₃) δ 7.58 (m, 4H), 7.40 (m, 4H), 4.64 (t, J=6 Hz, 1H),2.34 (m,1H), 2.10 (m and solvent), 1.74 (m, 1H), 1.54 (m, 2H), 1.28 (m,2H), 0.87 (d, J=6 Hz, 3H), 0.77 (d, J=6 Hz, 3H). ##STR61##

EXAMPLE 28 AND EXAMPLE 29 (Reference with respect to composition)

The lactones Example 28 and Example 29 were prepared by dissolving amixture of Example 26 and Example 27 (51 mg) in 25 ml benzene along withcamphor sulfonic acid (11 mg). This mixture was refluxed for 12 hoursusing a Dean-Stark trap. The resultant solution was washed with aqueoussodium bicarbonate, dried over MgSO₄ and evaporated in vacuo. Theresidue was purified by Silica gel chromatography with Hexane-EtOAc togive the separated lactones.

EXAMPLE 28

¹ H NMR (CDCl₃) δ 7.3-7.7 (m, 8H), 5.6 (m, 1H), 2.75 (m, 1H), 2.45(m,2H), 2.20 (solvent), 1.75 (m, 2H), 1.45 (m, 1H), 1.01 (d, J=7 Hz,3H), 0.87 (d, J=7 Hz, 3H); ¹³ C NMR (CDCl3) δ 180.24, 140.57, 139.98,139.51, 134.33, 129.68, 128.99, 127.98, 126.26, 79.98, 40.31, 37.73,37.53, 31.61, 26.83, 23.66, 22.27; MS (FAB-LSIMS) 329 M+H!⁺ (C₂₀ H₂₁ O₂Cl FW=328.87).

EXAMPLE 29

¹ H NMR (CDCl3) δ (m, 8H), (m, 1H), (m, 1H), 2 (m,2H), 2.20 (solvent),1.75 (m, 2H), 1.45 (m, 1H), 1.01 (d, J=7 Hz,3H), 0.87 (d, J=7 Hz, 3H);MS (FAB-LSIMS) 328 M!⁺ (C₂₀ H₂₁ O₂ Cl FW=328.87). ##STR62##

EXAMPLE 30 (Reference with respect to composition)

4-Chlorobiphenyl (1.0667 g, 5.654 mmoles) was weighed into a 250 mLflask which had been purged with argon. Into this flask was transferreditaconic anhydride (637.4 mg, 5.686 mmoles) with1,1,2,2-tetrachloroethane (50 mL). The solution was cooled in an icebath and then aluminum trichloride (1.8141 g) was slowly added as asolid. The ice bath was removed and the reaction was allowed to warm toroom temperature. The reaction was stirred at room temperature for 24hours, cooled in an ice bath and quenched with 10% HCL solution (200mL). The aqueous mixture was extracted thrice with chloroform. Thecombined organic extracts were washed with saturated sodium bicarbonatewhich was then acidified with concentrated hydrochloric acid. Theaqueous mixture was extracted thrice with chloroform and the combinedorganic extracts washed once with brine. The solution was dried overMgSO₄ and concentrated in vacuo. The white solid was recrystallized(hexane-ethyl acetate) to provide 598.8 mg of fluffy white solid Example30 (mp=169°-170° C.).

TLC (methylene chloride-5%methanol) R_(f) 0.14; ¹ H NMR (DMSO-d6) δ12.50 (bs, 0.6 H), 8.05 (d, J=8.8 Hz, 2 H), 7.83 (d, J=8.06 Hz, 2 H),7.78 (d, J=8.07 Hz, 2 H), 7.55 (d, J=8.8 Hz, 2 H), 6.21 (d, J=1.46 Hz ,1H), 5.74 (bs, 1 H), 4.06 (bs, 2 H); ¹³ C NMR (DMSO-d₆) δ 197.73, 168.62,144.30, 138.76, 137.10, 136.49, 134.45, 130.17, 129.91, 129.10, 128.02,42.74, 40.19; MS (FAB-LSIMS) 301 M+H!⁺ (C₁₇ H₁₃ O₃ Cl, FW=300.57); Anal.C: calcd, 67.89; found, 67.76. H: calcd, 4.36; found, 4.34. Cl: calcd,11.79; found, 11.82.

EXAMPLE 31 AND EXAMPLE 32

The general method of Example 30 was used to prepare Example 31 andExample 32 by using either toluene or 2-chlorobiphenyl instead of4-chlorobiphenyl as indicated below. ##STR63##

EXAMPLE 31 (Reference)

From toluene: MP: 144.0°-145.5° C.; ¹ H NMR (MeOD-_(d3)) δ 7.88 (d, J=8Hz, 2 H), 7.29 (d, J=8 Hz, 2 H), 6.32 (s, 1H), 5.70 (s, 1 H), 4.00 (s, 2H), 2.39 (s, 3H); ¹³ C NMR (MeOD-_(d3)) δ 198.24, 169.01, 144.78,136.40, 134.66, 129.59, 128.68, 128.25, 41.91, 20.87; MS (FAB-LSIMS) 205M+H!⁺ (C₁₂ H₁₂ O₃, FW=204.23); Anal. C: calcd, 70.58; found, 70.62. H:calcd, 5.92; found, 5.93. ##STR64##

EXAMPLE 32 (Reference with respect to composition)

From 2-chlorobiphenyl: MP: 186.0°-187.5° C.; ¹ H NMR (DMSO-_(d6)) δ 12.6(bs, 1H), 8.05 (d, J=8 Hz, 2 H), 7.4-7.6 (m, 6H), 6.21 (s, 1H), 5.74 (s,1 H), 4.07 (s, 2 H); ¹³ C NMR (DMSO-_(d6)) δ 197.84, 168.64, 144.45,139.89, 137.06, 136.58, 132.46, 132.24, 131.06, 130.93, 130.78, 129.09,128.75, 120.00, 42.75; MS (FAB-LSIMS) 301 M+H!⁺ (C₁₇ H₁₃ O₃ Cl,FW=300.74); Anal. C: calcd, 67.89; found, 67.49. H: calcd, 4.36; found,4.39.

EXAMPLE 33 and EXAMPLE 34

These compounds were prepared by a similar method to that used forExample 30, except that the indicated anhydrides were used instead ofitaconic anhydride. ##STR65##

EXAMPLE 33 (Reference with respect to composition)

From 2-methylsuccinic anhydride: MP 196°-197° C.; TLC (methylenechloride-10% methanol) R_(f) 0.566; ¹ H NMR (DMSO-d₆) δ 12.13 (s, 1 H),8.03 (d, J=8.22 Hz, 2 H), 7.79 (m, 4 H), 7.54 (m, 2 H), 3.40 (m, 1 H),3.07 (m, 1 H), 2.88 (m, 1 H), 1.16 (d, J=7.16 Hz, 3 H); ¹³ C NMR(DMSO-d₆) δ 199.00, 177.91, 144.24, 138.76, 136.61, 134.42, 130.15,129.88, 129.75, 127.99, 42.64, 35.60, 18.17; MS (FAB-LSIMS) 303 M+H!⁺(C₁₇ H₁₅ O₃ Cl, FW=302.76); Anal. C: calcd, 67.44; found, 67.41. H:calcd, 4.99; found, 5.00. Cl: calcd, 11.71;

found, 11.69. ##STR66##

EXAMPLE 34 (Reference with respect to composition)

From maleic anhydride: ¹ H NMR (DMSO-d₆) δ 13.25 (s, 1 H), 8.10 (d, J=8Hz, 2H), 7.75-7.95 (m, 6H), 7.55 (d, J=8 Hz, 2H), 6.7 (d, J=16 Hz, 1H);¹³ C NMR (DMSO-d₆) δ 190.0, 167.2, 144.8, 138.8, 137.2, 136.4, 134.8,134.0, 130.8, 130.5, 128.0; MS (FAB-LSIMS) 287 M+H!⁺ (C₁₆ H₁₁ O₃ Cl,FW=286.76).

EXAMPLE 35 (Reference)

This compound was prepared by a similar method to that used for Example30, except that maleic anhydride was used instead of itaconic anhydrideand 4-chlorodiphenyl ether was used instead of 4-chlorobiphenyl.##STR67##

EXAMPLE 35

MP: 155.0°-157.0° C.; ¹ H NMR (MeOD-d₃) δ 8.03 (d, J=9 Hz, 2H), 7.92 (d,J=15 Hz, 1H), 7.41 (d, J=9 Hz, 2H), 7.1-7.0 (m, 4H), 6.75 (d, J=15 Hz,1H); MS (FAB-LSIMS) 302 M+H!⁺ (C₁₆ H₁₁ O₄ Cl, FW=280.27). ##STR68##

EXAMPLE 36

This compound was prepared in a similar manner to Example 1, except thatthe indicated anhydride was used instead ofdihydro-3-(2-methylpropyl)-2,5-furandione. From 2-n-pentylsuccinicanhydride. This anhydride was prepared according to the procedures givenfor dihydro-3-(2-methylpropyl)-2,5-furandione, except that valeraldehydewas used instead of isobutyraldehyde.

MP 141°-142° C.; TLC (methylene chloride-10% methanol) R_(f) 0.563; ¹ HNMR (DMSO-d₆) δ 12.22 (bs, 0.5 H), 8.05 (d, J=8.36 Hz, 2 H), 7.79 (m, 4H), 7 54 (d, J=8.6 Hz, 2 H), 3.38 (m, 1 H), 3.09 (m, 1 H), 2.81 (m, 1H), 1.40 (m, 8 H), 0.84 (t, J=6.69 Hz, 3 H); ¹³ C NMR: (DMSO-d₆) δ199.21, 177.42, 144.24, 136.63, 130.17, 129.90, 129.78, 127.97, 41.09,40.97, 32.57, 32.29, 27.26, 23.06, 15.00; MS (FAB-LSIMS) 359 M+H!⁺ (C₂₁H₂₃ O₃ Cl, FW=358.87); Anal. C: calcd, 70.29; found, 70.54. H: calcd,6.46; found, 6.47. Cl: calcd, 9.88; found, 10.15. ##STR69##

EXAMPLE 37 (Intermediate)

The general method of Example 30 was used to prepare Example 37 by usingacetyl chloride instead of itaconic anhydride. The neutral productremained in the chloroform layer after sodium bicarbonate wash. Thisproduct-containing solution was treated with activated carbon, filteredand then evaporated. The resultant residue was recrystallized from ethylacetate and hexane to yield product melting at 100°-101° C.

TLC (methylene chloride-2% methanol) R_(f) 0.735; ¹ H NMR (CDCl₃) δ 8.04(d, J=8.60 Hz, 2H), 7.65 (d, J=8.84 Hz, 2H), 7.56 (d, J=8.60 Hz, 2H),7.45 (d, J=8.84 Hz, 2H), 2.65 (s, 3H); ¹³ C NMR (CDCl₃) δ 197.62,144.44, 138.27, 136.04, 134.43, 129.13, 128.99, 128.49, 127.05, 26.66;MS (FAB-LSIMS) 231 M+H!⁺ (C₁₄ H₁₁ OCl, FW=230.69); Anal. C: calcd,72.89; found, 72.91. H: calcd, 4.81; found, 4.74. Cl: calcd, 15.37;found, 15.11. ##STR70##

EXAMPLE 38 (Reference with respect to composition)

Example 30 (97.9 mg, 0.325 mmol) was dissolved in 1.0 ml of a 0.446Msolution of potassium hydroxide in water. Slowly, 76.8 mg (2.030 mmol)of sodium borohydride was added. The mixture was stirred at roomtemperature for 15 hours. The reaction was quenched by addition of 6NHCl and extracted twice with ethyl acetate and the combined organicextracts washed once with brine. The solution was dried over MgSO₄ andconcentrated in vacuo. The white solid was recrystallized (hexane-ethylacetate) to provide 57.1 mg of white solid Example 38 (mp=118°-120° C.).

TLC (methylene chloride-5% methanol) R_(f) 0.192; ¹ H NMR (DMSO-d₆) δ12.25 (bs, 1 H), 7.66(d, J=8.07 Hz, 2 H), 7.60 (d, J=8.8 Hz, 2 H), 7.48(d, J=8.07 Hz, 2 H), 7.37 (d, J=8.07 Hz, 2 H), 6.02 (bd, J=1.47 Hz, 1H), 5.53 (bs, 1 H), 5.3 (bs, 1 H), 4.72 (t, J=6.6 Hz, 1 H), 2.53 (d,J=5.87 Hz, 2 H); ¹³ C NMR (DMSO-d₆) δ 129.94, 129.39, 127.64, 127.33,71.98, 42.92. Weak signal to noise; these were the only distinguishablepeaks. MS (FAB-LSIMS) 285 M+H!⁺ (lactone formed during ionization) (C₁₇H₁₅ O₃ Cl, FW=302.76); Anal. C: calcd, 67.44; found, 66.77. H: calcd,4.99; found, 4.94. Cl: calcd, 11.71; found, 11.31. ##STR71##

EXAMPLE 39 (Reference with respect to composition)

Example 39 was prepared from Example 9 in a way similar to thepreparation of Example 38.

¹ H NMR (DMSO-d₆) δ 12.1 (bs, 1 H), 7.66(d, J=8.07 Hz, 2 H), 7.2-7.6 (m,8H), 5.3 (d, J=4 Hz, 1 H), 4.6 (m, 1 H), 2.3 (t, J=7 Hz, 2H), 2.8 (d,2H); ¹³ C NMR (DMSO-d₆) δ 176.37, 162.63, 159.37, 147.40, 135.39,132.64, 132.59, 131.33, 131.22, 130.43, 130.40, 130.15, 129.98, 127.89,126.84, 126.79, 118.12, 117.83, 72.92, 36.24, 32.21; MS (FAB-LSIMS) 257M+H!⁺ (lactone formed during ionization) (C₁₆ H₁₅ O₃ F, FW=274.28);Anal. C: calcd, 67.83; found, 67.80. H: calcd, 5.12; found, 5.50, withcalcd 0.5 H₂ O.

EXAMPLE 40 ##STR72## Step 1--Preparation of 4-lodobiphenyl.

A solution of trimethyltin chloride (5.5 g, 27.60 mmoles) in 5 mL of DMEwas added to a stirred suspension of small cubes of metallic sodium (1.9g, 82.64 mg atom) in 15 mL of DME under an argon stream in an ice bath.When the addition was complete, the mixture was stirred and chilled inan ice bath for 2 hrs. (the color changed to green). The mixture wascannulated into another dry and under argon round bottom flask to removeexcess sodium and cooled to 0° C. A solution of 4-bromobiphenyl (5.4 g,22.70 mmoles) in 14 mL of DME was added dropwise to the chilled NaSnMe₃solution. The resulting solution was stirred at room temperatureovernight at which time TLC analysis showed complete reaction. R_(f) ofthe trimethyltin product=0.44 (silica, hexanes). The reaction mixturewas then cooled in an ice bath and treated with iodine (6.6 g, 26.00mmoles). After stirring at room temperature for 1.5 hrs, the mixture wasdiluted with EtOAc, washed with water, brine, dried over MgSO₄, and thesolvent removed at reduced pressure. The crude product was then purifiedby column chromatography with hexanes to afford 5.5 g (86% yield) ofwhite solid.

TLC (silica, hexanes) R_(f) =0.54; ¹ H NMR (CDCl₃) δ 7.78 (d, J=8.70 Hz,2H), 7.32-7.59 (m, 6H); ¹³ C NMR (CDCl₃) δ 140.69, 140.02, 137.80,128.99, 128.89, 127.68, 126.87, 93.02. ##STR73## Step 2--Preparation of2-Bromo-4-(4-Iodophenyl)-acetophenone.

A solution of 4-iodobiphenyl from step 1 (1.35 g, 4.82 mmoles) in 25 mLof dry dichloroethane was treated with bromoacetyl bromide (0.47 mL,5.21 mmoles) and cooled to 0° C. under a stream of argon. The cooledmixture was then treated with AlCl₃ (0.77 g, 5.77 mmoles) and allowed tostir at room temperature overnight. The reaction mixture was poured intocold 10% HCl and extracted thrice with methylene chloride. The combinedextracts were then washed with brine, dried over MgSO₄, and concentratedat reduced pressure. Crystallization from EtOAc/hexanes afforded 1.1 g(58% yield) as light brown fine needles.

¹ H NMR (CD₃ OD) δ 8.17 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.94(d, J=8.7 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 5.05 (s, 2H); ¹³ C NMR (CD₃OD) δ 200.86, 153.56, 147.68, 147.43, 142.61, 139.12, 138.71, 136.40,104.93, 43.64. ##STR74## Step 3

A solution of diethyl-(3-phenyl)propyl malonate (product of step 1 fromExample 87 preparation, 1.5 g, 5.28 mmoles) in 11 mL of dry THF wastreated with NaH (0.12 g, 4.95 mmoles) under a stream of argon. Themixture was stirred at room temperature for 30 min at which time ahomogenous mixture was obtained and the gas evolution ceased. A solutionof 2-bromo-4-(4-iodophenyl)-acetophenone from step 2 (1.85g, 4.61mmoles) in 20 mL of dry THF was added and the reaction mixture wasallowed to stir at room temperature for 4 hrs, at which time a TLCanalysis showed complete reaction. The mixture was then quenched with 2NHCl, diluted with EtOAc, and the layers were separated. The aqueouslayer was extracted twice with EtOAc and the combined Extracts werewashed with brine, dried over MgSO₄, and the solvent removed at reducedpressure. The crude product was chromatographed with a gradient 3%-40%EtOAc in hexanes to afford 2.28 g (83% yield) of pure product.

TLC (silica, EtOAc:hexanes, 1:4) R_(f) =0.37; ¹ H NMR (CDCl₃) δ 8.03 (d,J=9 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.36 (d,J=8.4 Hz, 2H), 7.10-7.24 (m, 5H), 4.20 (q, J=7.2 Hz, 4H), 3.70 (s, 2H),2.60 (t, J=7.6 Hz, 2H), 2.16-2.22 (m, 2H), 1.54-1.59 (m, 2H), 1.23 (t,J=7.2 Hz, 6H); ¹³ C NMR (CDCl₃) δ 196.12, 170.88, 144.78, 141.65,139.27, 138.08, 135.62, 129.00, 128.73, 128.28, 126.98, 125.84, 124.63,119.57, 94.33, 61.51, 55.37, 41.28, 35.85, 32.70, 26.63, 13.97.##STR75## Step 4

A solution of the diethylester from step 3 (2.28 g, 3.81 mmoles) in THF(5 mL)/EtOH (15 mL) was treated with 5 eq of NaOH in 5 mL of water andallowed to stir at room temperature overnight. At this time, thereaction mixture was acidified with 2N HCl and the solvent removed atreduced pressure. The solid formed was then filtered, washed with water,and dried to afford 1.6 g (77%) of pure product.

TLC (silica,CH₂ Cl₂ :MeOH, 9:1) R_(f) =0.14; ¹ H NMR (DMSO-d₆) δ 8.01(d, J=7.8 Hz, 2H), 7.78-7.86 (m, 4H), 7.54 (d, J=8.4 Hz, 2H), 7.08-7.23(m, 5H), 3.61 (s, 2H), 2.51 (t, J=7.5 Hz, 2H), 1.92-1.98 (m, 2H),1.45-1.55 (m, 2H); ¹³ C NMR (DMSO-d₆) δ 196.90, 172.65, 143.72, 141.85,138.50, 138.07, 135.73, 129.32, 128.41, 126.96, 125.91, 95.37, 54.64,41.43, 35.47, 32.93, 26.43. ##STR76## Step 5--Preparation of Example 40.

The diacid from step 4 (1.6 g, 2.95 mmoles) was dissolved in 30 mL of1,4-dioxane and refluxed for 36 hrs. The reaction mixture was thencooled to room temperature and the solvent removed at reduced pressure.The residue obtained was crystallized from EtOAc/hexanes to afford 0.6 g(41% yield).

MP. 165°-165.5° C.; TLC (silica, CH₂ Cl₂ :MeOH, 9:1) R_(f) =0.41; ¹ HNMR (CDCl₃ -CD₃ OD) δ 7.96 (d, J=9 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.57(d, J=8.7 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.08-7.24 (m, 5H), 3.42 (m,1H), 2.95-3.06 (m, 2H), 2.57-2.64 (m, 2H), 1.57-1.78 (m, 4H); ¹³ C NMR(CDCl₃ -CD₃ OD) δ 198.24, 177.71, 144.60, 141.81, 139.13, 137.93,135.48, 128.86, 128.62, 128.23, 128.18, 126.85, 125.66, 94.14, 40.26,39.94, 35.48, 31.46, 28.76; MS (FAB-LSIMS) 498.9 M+H!⁺ (C₂₅ H₂₃ IO₃,FW=498.365); HRMS for C₂₅ H₂₄ IO₃ calcd. 499.07702; found 499.07782;Anal. C: calcd, 60.25; found, 60.23. H: calcd, 4.65; found, 4.63.##STR77##

EXAMPLE 41

This compound was prepared in a similar manner to Example 40, exceptthat the diethyl isobutyl malonate was used instead ofdiethyl-(3-phenyl)propyl malonate.

TLC (methylene chloride--10% methanol) R_(f) 0.54; ¹ H NMR (CDCl₃) δ8.04 (d, J=8.2 Hz, 2H), 7.81 (d, J=8.2 Hz, 2H), 7.64 (d, J=7,9 Hz, 2H),7.36 (d, J=8.5 Hz, 2H), 3.46 (dd, J₁ =17.1 Hz, J₂ =8.5 Hz, 1H),3.19-3.11 (m, 1H), 1.76-1.65 (m, 2H), 1.49-1.36 (m, 1H), 0.99 (d, J=5.9Hz, 3H), 0.93 (d, J=5.9 Hz, 3H); ¹³ C NMR (CDCl₃) δ 197.51, 181.34,144.70, 139.27, 138.05, 135.50, 128.99, 128.73, 126.98, 94.30, 41.08,40.62, 38.29, 25.85, 22.49, 22.30; MS (FAB-LSIMS) 437 M+H!⁺ ; HRMS (FAB)calcd. for C₂₀ H₂₂ IO₃ M+H!⁺ 437.06137, found 481.06052; ElementalAnalysis calcd. C 55.06, H 4.85; found C 54.90, H 4.79. ##STR78##

EXAMPLE 42

Example 40 (300 mg, 0.60 mmole) was dissolved in DMF (3 mL) and treatedwith ethyl acrylate (0.15 mL, 1.38 mmoles), Pd(OAc)₂ (15 mg, 0.07mmole), sodium bicarbonate (126 mg, 1.50 mmoles), and tetrabutylammoniumchloride (69 mg, 0.24 mmole). The mixture was refluxed for 3 days atwhich time it was diluted with ethyl acetate and transferred to aseparatory funnel. The organic layer was washed with water, brine, driedover MgSO₄, and the solvent removed at reduced pressure. The crudeproduct was chromatographed with 0-4% methanol in methylene chloride toafford 120 mg of product.

MP 155°-157° C.; TLC (methylene chloride--5% methanol) R_(f) 0.24; ¹ HNMR (CDCl₃) δ 8.04 (d, J=8.3 Hz, 2H), 7.76-7.58 (m, 7H), 7.31-7.16 (m,5H), 6.50 (d, J=16.09 Hz, 1H), 4.29 (q, J=6.9 Hz, 2H), 3.49 (dd, J₁=16.7 Hz, J₂ =8.0 Hz, 1H), 3.17-3.05 (m, 2H), 2.67 (t, J=7.2 Hz, 2H),1.86-1.66 (m, 4H), 1.36 (t, J=7.2 Hz, 3H); ¹³ C NMR (CDCl₃) δ 197.49,179.63, 166.92, 144.86, 143.73, 141.78, 141.41, 135.51, 134.41, 128.74,128.65, 128.39, 128.36, 127.69, 127.16, 125.87, 118.78, 60.61, 40.23,39.81, 35.62, 31.44, 28.89, 14.31; MS (FAB-LSIMS) 471 M+H!⁺. ##STR79##

EXAMPLE 43

A suspension of Example 42 (28 mg, 0.06 mmole) in ethanol (1.5 mL) wastreated with a solution of NaOH (14 mg, 0.35 mmole) in water (0.3 mL)and the mixture was stirred at room temperature overnight. At this time,it was quenched with 2N HCl and extracted with methylene chloride (2×10mL). The combined extracts were washed with brine, dried over MgSO₄, andthe solvent removed at reduced pressure to afford 23 mg (87%) ofproduct.

MP 230°-232° C.; TLC (methylene chloride--5% methanol) R_(f) 0.05; ¹ HNMR (CDCl₃ /DMSO-d₆) δ 7.87 (d, J=8.3 Hz, 2H), 7.57-7.45 (m, 7H),7.13-7.00 (m, 5H), 6.32 (d, J=15.8 Hz, 1H), 3.33 (dd, J₁ =17.9 Hz, J₂=9.2 Hz, 1H), 2.92-2.84 (m, 2H), 2.51-2.46 (m, 2H), 1.65-1.49 (m, 4H);¹³ C NMR (CDCl₃ /DMSO-d₆) δ 197.38, 176.79, 168.12, 144.12, 143.20,141.62, 140.81, 135.38, 134.04, 128.26, 128.20, 127.95, 127.84, 127.21,126.63, 125.30, 119.04, 40.05, 39.75, 35.25, 31.25, 28.58; MS(FAB-LSIMS) 443 M+H!⁺. ##STR80##

EXAMPLE 44

A solution of Example 42 (60 mg, 0.13 mmole) in ethanol (2 mL) wastreated with 10% Pd on C (10 mg) and the mixture was stirred at roomtemperature overnight under hydrogen gas balloon. At this time, thereaction mixture was filtered through celite and the solvent was removedat reduced pressure to afford 43 mg of product as oil.

TLC (methylene chloride--5% methanol) R_(f) 0.33; ¹ H NMR (CDCl₃) δ7.53-7.48 (m, 4H), 7.30-7.15 (m, 9H), 4.15 (q, J=6.9 Hz, 2H), 2.99 (t,J=8.0 Hz, 2H), 2.72-2.59 (m, 6H), 2.51-2.45 (m, 1H), 2.10-1.95 (m, 1H),1.83-1.58 (m, 5H), 1.25 (t, J=6.9 Hz, 3H); ¹³ C NMR (CDCl₃) δ 180.63,172.95, 141.92, 140.40, 139.45, 138.98, 138.68, 128.83, 128.70, 128.36,128.32, 127.03, 126.97, 125.82, 60.45, 44.51, 35.88, 35.67, 33.70,33.14, 31.68, 30.57, 28.95, 14.21; MS (FAB-LSIMS) 458 M!⁺. ##STR81##

EXAMPLE 45

A suspension of Example 44 (15 mg, 0.03 mmole) in ethanol (1 mL) wastreated with a solution of sodium hydroxide (9 mg, 0.23 mmole) in water(0.2 mL) and allowed to stir at room temperature for 1.5 days. Thereaction mixture was then quenched with 2N HCl, diluted with ethylacetate and the layers were separated. The organic layer was washed withbrine, dried over MgSO₄, and the solvent was removed at reduced pressureto afford 12 mg of product.

MP 131°-132° C.; ¹ H NMR (CDCl₃) δ 7.52 (d, J=8.0 Hz, 2H), 7.48 (d,J=7.7 Hz, 2H), 7.30-7.15 (m, 9H), 2.87 (t, J=7.7 Hz, 2H), 2.78-2.40 (m,7H), 2.10-1.98 (m, 1H), 1.91-1.81 (m, 1H), 1.78-1.53 (m, 4H); ¹³ C NMR(CDCl₃) δ 181.97, 178.53, 141.92, 140.07, 138.97, 138.92, 138.45,129.10, 128.58, 128.36, 128.32, 126.95, 126.69, 125.82, 45.02, 35.66,35.04, 33.62, 33.49, 31.94, 29.99, 28.95; MS (FAB-LSIMS) 430 M!⁺.##STR82##

EXAMPLE 46

Example 41 (50 mg, 0.12 mmoles), Cu(I)CN (36 mg, 0.40 mmoles), and 0.7mL of 1-methyl-2-pyrrolidinone were mixed and heated at 125° C. for 24hr. The reaction mixture was diluted with methylene chloride andevaporated at reduced pressure. The crude product was thenchromatographed with 0-8% methanol in methylene chloride on the MPLC toafford 26.5 mg (66% yield) of product.

TLC (methylene chloride--10% methanol) R_(f) 0.48; ¹ H NMR (CDCl₃ /CD₃OD) δ 8.06 (d, J=8.2 Hz, 2H), 7.65-7.76 (m, 6H), 3.45 (dd, J₁ =17.0 Hz,J₂ =7.9 Hz, 1H), 3.04-3.10 (m, 2H), 1.64-1.75 (m,2H), 1.38-1.42 (m, 1H),0.96 (d, J=5.9 Hz, 3H), 0.91 (d, J=6.2 Hz, 3H); ¹³ C NMR (CDCl₃ /CD₃ OD)δ 197.96, 178.20, 144.20, 143.49, 136.29, 132.64, 128.74, 127.81,127.34, 118.52, 111.63, 53.34, 41.16, 40.82, 25.79, 22.36, 22.24; MS(FAB-LSIMS) 336 M+H!⁺ ; HRMS (FAB) calcd. for C₂₁ H₂₂ NO₃ S M+H!⁺336.15997, Found 336.16129.

EXAMPLE 47 ##STR83## Step 1

This intermediate was prepared in a similar manner to Example 40 except2,4'-dibromoacetophenone was used instead of2-bromo-4-(4-iodophenyl)acetophenone. TLC (methylene chloride--10%methanol) R_(f) 0.52;

¹ H NMR (CDCl₃) δ 7.82 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H),7.31-7.16 (m, 5H), 3.41 (dd, J₁ =17.1 Hz, J₂ =8.5 Hz, 1H), 3.15-3.06 (m,1H), 2.99 (dd, J₁ =17.1 Hz, J₂ =4.4 Hz, 1H), 2.66 (t, J=7.4 Hz, 2H),1.83-1.63 (m, 4H); ¹³ C NMR (CDCl₃) δ 196.90, 181.13, 141.66, 135.09,131.89, 129.52, 128.47, 128.34, 125.85, 39.94, 39.89, 35.54, 31.33,28.79. ##STR84## Step 2

Methylation of the product from step 1 with diazomethane in ethanolafforded quantitative yield of the methyl ester. TLC (hexanes, 10% ethylacetate) R_(f) 0.21;

¹ H NMR (CDCl₃) δ 7.82 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H),7.32-7.16 (m, 5H), 3.70 (s, 3H), 3.43 (dd, J₁ =16.8 Hz, J₂ =8.5 Hz, 1H),3.13-3.05 (m, 1H), 3.98 (dd, J₁ =17.1 Hz, J₂ =4.4 Hz, 1H), 2.65 (t,J=7.1 Hz, 2H), 1.80-1.59 (m, 4H); ¹³ C NMR (CDCl₃) δ 197.15, 175.82,141.79, 135.25, 131.89, 129.54, 128.41, 128.34, 125.87, 51.84, 40.37,40.07, 35.59, 31.68, 28.91. ##STR85## Step 3

The product from step 2 (1.85 g, 4.75 mmoles), hexamethyiditin (2.00 g,5.80 mmoles), and palladium tetrakistriphenylphosphine (44 mg, 0.038mmoles) in 7 mL of toluene were refluxed for 3 hr under argon. TLCshowed complete reaction. The reaction mixture was then cooled to roomtemperature, the solvent was removed at reduced pressure, and theresidue was chromatographed on the MPLC with 3-30% ethyl acetate inhexanes to afford 2.25 g (100% yield) of the trimethyltin product.

TLC (hexanes--10% ethyl acetate) R_(f) 0.26; ¹ H NMR (CDCl₃) δ 7.77 (d,J=7.9 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.21-7.05 (m, 5H), 3.33 (dd, J₁=16.2, J₂ =7.4 Hz, 1H), 3.01-2.89 (m, 2H), 2.56-2.51 (m, 2H), 1.66-1.47(m, 4H), 0.22 (s, 9H); ¹³ C NMR (CDCl₃) δ 197.15, 175.97, 150.37,141.87, 136.17, 135.98, 128.34, 128.31, 126.89, 125.81, 51.76, 40.42,40.13, 35.59, 31.73, 28.94, -9.58. ##STR86## Step 4

4-Bromo-N-Boc-aniline (0.61 g, 2.24 mmoles), the product from step 3(0.51 g, 1.08 mmoles), and palladium tetrakistriphenylphosphine (94 mg,0.08 mmoles) in 9 mL of toluene were refluxed for 3 hr under argon.After TLC showed complete reaction, the reaction mixture was filtered,concentrated at reduced pressure, and chromatographed with 3-60% ethylacetate in hexanes to afford 180 mg of product (33% yield) as the methylester.

TLC (hexanes--20% ethyl acetate) R_(f) 0.26; ¹ H NMR (CDCl₃) δ 8.00 (d,J=8.2 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.47 (d,J=8.5 Hz, 2H), 7.32-7.16 (m, 5H), 3.71 (s, 3H), 3.52-3.43 (m, 1H),3.14-3.03 (m, 2H), 2.66 (t, J=7.1 Hz, 2H), 1.78-1.60 (m, 4H), 1.55 (s,9H). ##STR87## Step 5--Preparation of Example 47

The methyl ester (93 mg) was dissolved in 3 mL of ethanol and treatedwith 5 eq of sodium hydroxide in 0.5 mL of H₂ O. The mixture was stirredat room temperature for 10 hr at which time TLC showed completehydrolysis of the methyl ester. The reaction mixture was acidified with2N HCl, diluted with ethyl acetate, and the layers were separated. Theorganic layer was washed with brine, dried over MgSO₄, and the solventremoved at reduced pressure to afford 82 mg of product.

MP 169°-171° C.; TLC (methylene chloride--4% methanol) R_(f) 0.24; ¹ HNMR (CDCl₃ /DMSO-d₆) δ 7.92 (d, J=8.2 Hz, 2H), 7.88 (s, 1H), 7.57 (d,J=8.2 Hz, 2H), 7.48 (broad s, 3H), 7.21-7.07 (m, 5H), 3.40 (dd, J₁ =18.5Hz, J₂ =9.7 Hz, 1H), 3.01-2.92 (m, 2H), 2.60-2.51 (m, 2H), 1.72-1.58 (m,4H), 1.48 (m, 9H); ¹³ C NMR (CDCl₃ /DMSO-d₆) δ 197.46, 176.94, 152.66,144.86, 141.70, 139.06, 134.59, 133.28, 128.26, 128.02, 127.90, 127.18,126.16, 125.35, 118.49, 40.07, 39.84, 35.33, 31.35, 28.65, 28.05; MS(FAB-LSIMS) 488 M+H!⁺ ; Elemental Analysis calcd. for C₃₀ H₃₃ NO₅ C73.90, H 6.82, N 2.87; Elemental Analysis found. C 73.55, H 6.89, N2.61.

EXAMPLE 48, EXAMPLE 49, EXAMPLE 50, EXAMPLE 51, EXAMPLE 52, EXAMPLE 53,EXAMPLE 54, EXAMPLE 55 and EXAMPLE 56

These compounds were prepared in a similar manner to Example 47, exceptthat the indicated bromides were used instead of 4-bromo-Boc-aniline instep 4: ##STR88##

EXAMPLE 48

From 1-Bromo-t-butyl benzene: MP 124°-125° C.; TLC (methylenechloride--10% methanol) R_(f) 0.48; ¹ H NMR (CDCl₃) δ 7.94 (d, J=8.2 Hz,2H), 7.61 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz,2H), 7.23-7.09 (m, 5H), 3.41 (dd, J₁ =17.1 Hz, J₂ =8.2 Hz, 1H),3.11-2.99 (m, 2H), 2.59 (t, J=7.1 Hz, 2H), 1.78-1.58 (m, 4H), 1.30 (s,9H); ¹³ C NMR (CDCl₃) δ 197.61, 179.83, 151.50, 145.86, 141.81, 136.85,134.88, 128.63, 128.37, 128.34, 127.02, 126.90, 125.92, 125.84, 40.18,39.85, 35.62, 34.62, 31.44, 31.28, 28.91; MS (FAB-LSIMS) 429 M+H!⁺ ;HRMS (FAB) calcd. for C₂₉ H₃₃ O₃ M+H!⁺ 429.24297, Found 429.24094.##STR89##

EXAMPLE 49

From 4-bromo-N-Boc-benzylamine: MP 156° C.; TLC (hexanes--50% ethylacetate) R_(f) 0.24; ¹ H NMR (CDCl₃) δ 8.03 (d, J=6.5 Hz, 2H), 7.67 (d,J=6.5 Hz, 2H), 7.60 (d, J=5.9 Hz, 2H), 7.40 (d, J=5.3 Hz, 2H), 7.32-7.19(m, 5H), 4.95 (broad s, 1H), 4.40 (broad s, 2H), 3.49 (dd, J₁ =17.3 Hz,J₂ =7.9 Hz, 1H), 3.20-3.08 (m, 2H), 2.69 (t, J=5.2 Hz, 2H), 1.86-1.69(m, 4H), 1.50 (s, 9H); MS (FAB-LSIMS) 502 M+H!⁺ ; HRMS (FAB) calcd. forC₃₁ H₃₆ NO₅ M+H!⁺ 502.25935, Found 502.25906; Elemental Analysis calcd.C 74.23, H 7.03, N 2.79; found. C 73.93, H 7.10, N 2.55. ##STR90##

EXAMPLE 50

From 4-bromophenyl acetonitrile: MP 139°-140° C.; TLC (hexanes--70%ethyl acetate) R_(f) 0.42; ¹ H NMR (CDCl₃ /DMSO-d₆) δ 7.98 (d, J=8.2 Hz,2H), 7.60 (d, J=8.2 Hz, 2H), 7.58 (d, J=7.9 Hz, 2H), 7.38 (d, J=7.9 Hz,2H), 7.23-7.08 (m, 5H), 3.77 (s, 2H), 3.43 (dd, J₁ =16.2 Hz, J₂ =7.1 Hz,1H), 3.07-2.94 (m, 2H), 2.64-2.57 (m, 2H), 1.79-1.58 (m, 4H); ¹³ C NMR(CDCl₃ /DMSO-d₆) δ 197.62, 177.18, 144.41, 141.84, 139.50, 135.54,129.75, 128.49, 128.36, 128.18, 128.07, 127.71, 126.90, 125.53, 119.41,40.27, 39.95, 35.49, 31.47, 28.79, 23.11; MS (FAB-LSIMS) 412 M+H!⁺ ;HRMS (FAB) calcd. for C₂₇ H₂₆ NO₃ M+H!⁺ 412.19127, Found 412.18979;Elemental Analysis calcd. C 78.81, H 6.12, N 3.40; found. C 78.45, H6.14, N 3.22. ##STR91##

EXAMPLE 51

From 4-bromothioanisole: MP 174.5°-175° C.; TLC (hexanes--50% ethylacetate) R_(f) 0.32; ¹ H NMR (CDCl₃ /DMSO-d₆) δ 7.62 (d, J=7.9 Hz, 2H),7.28 (d, J=7.9 Hz, 2H), 7.18 (d, J=7.9 Hz, 2H), 6.94 (d, J=7.9 Hz, 2H),6.89-6.74 (m, 5H), 3.07 (dd, J₁ =17.9 Hz, J₂ =9.7 Hz, 1H), 2.67-2.61 (m,2H), 2.30-2.23 (m, 2H), 2.13 (s, 3H), 1.40-1.23 (m, 4H); ¹³ C NMR (CDCl₃/DMSO-d₆) δ 196.72, 176.03, 143.76, 141.00, 138.17, 135.03, 134.28,127.66, 127.37, 127.29, 126.47, 125.66, 125.55, 124.76, 39.42, 39.15,34.64, 30.63, 28.02, 14.37; MS (FAB-LSIMS) 419 M+H!⁺ ; HRMS (FAB) calcd.for C₂₆ H₂₇ SO₃ M+H!⁺ 419.16809, Found 419.16895; Elemental Analysiscalcd. for C₂₆ H₂₆ SO₃.0.25H₂ O C 73.81, H 6.31; found C 73.51, H 6.23.##STR92##

EXAMPLE 52

From 4-bromophenyl-2-chloroethyl ether: MP 155°-156° C.; TLC(hexanes--50% ethyl acetate) R_(f) 0.12; ¹ H NMR (CDCl₃ /DMSO-d₆) δ 7.90(d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H),7.19-6.89 (m, 7H), 4.20 (t, J=5.9 Hz, 2H), 3.76 (t, J=5.9 Hz, 2H), 3.38(dd, J₁ =18.8 Hz, J₂ =8.8 Hz, 1H), 2.99-2.89 (m, 2H), 2.57-2.52 (m, 2H),1.73-1.54 (m,4H); ¹³ C NMR (CDCl₃ /DMSO-d₆) δ 197.54, 177.06, 158.20,144.78, 141.79, 134.74, 132.62, 128.37, 128.16, 128.12, 128.00, 126.32,125.45, 114.87, 67.83, 41.68, 40.16, 39.90, 35.43, 31.43, 28.74; MS(FAB-LSIMS) 451 M+H!⁺ ; HRMS (FAB) calcd. for C₂₇ H₂₈ CIO₄ M+H!⁺451.16761, Found 451.16565; Elemental Analysis calcd. for C₂₇ H₂₇CIO₄.0.25H₂ O C 781.20, H 5.98; found. C 71.21, H 6.10. ##STR93##

EXAMPLE 53

From 4-bromobenzyl alcohol: MP 165°-166° C.; TLC (hexanes--70% ethylacetate) R_(f) 0.21; ¹ H NMR (CDCl₃ /DMSO-d₆) δ 7.83 (d, J=7.9 Hz, 2H),7.49 (d, J=8.2 Hz, 2H), 7.42 (d, J=7.6 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H),7.10-6.97 (m, 5H), 4.51 (s, 2H), 3.28 (dd, J₁ =17.9 Hz, J₂ =7.9 Hz, 1H),2.88-2.80 (m, 2H), 2.49-2.43 (m, 2H), 1.62-1.48 (m, 4H); ¹³ C NMR (CDCl₃/DMSO-d₆) δ 197.59, 177.01, 145.19, 141.78, 138.24, 135.09, 128.34,128.11, 127.98, 127.12, 126.86, 126.71, 125.44, 63.84, 40.06, 39.80,35.41, 31.40, 28.74; MS (FAB-LSIMS) 403 M+H!⁺ ; HRMS (FAB) calcd. forC₂₆ H₂₇ O₄ M+H!⁺ 403.19093, Found 403.19165. ##STR94##

EXAMPLE 54

From 2-(4-bromophenoxy)ethanol: MP 167°-168° C.; TLC (methylenechloride--6% methanol) R_(f) 0.25; ¹ H NMR (CDCl₃ /DMSO-d₆) δ 7.80 (d,J=8.5 Hz, 2H), 7.4 4 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H),7.09-6.82 (m, 5H), 3.93 (t, J=4.7 Hz, 2H), 3.75 (t, J=4.7 Hz, 2H), 3.28(dd, J₁ =J₂ =9.7 Hz, 1H), 2.89-2.79 (m, 2H), 2.47-2.42 (m, 2H),1.62-1.433 (m, 4H); ¹³ C NMR (CDCl₃ /DMSO-d₆) δ 197.28, 176.73, 158.77,144.67, 141.54, 134.33, 131.60, 128.11, 127.86, 127.76, 125.97, 125.21,114.56, 69.12, 60.16, 39.66, 35.17, 31.17, 28.50; MS (FAB-LSIMS) 433M+H!⁺ ; HRMS (FAB) calcd. for C₂₇ H₂₉ O₅ M+H!⁺ 433.20150, Found433.20145. ##STR95##

EXAMPLE 55

From 4-bromostyrene: MP 156°-157° C.; TLC (methylene chloride--10%methanol R_(f) 0.47; ¹ H NMR (CDCl₃ /DMSO-d₆) δ 7.88 (d, J=7.6 Hz, 2H),7.54 (d, J=7.9 Hz, 2H), 7.46 (d, J=7.9 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H),7.14-6.99 (m, 5H), 6.61 (dd, J₁ =17.3 Hz, J₂ =10.5 Hz, 1H), 5.68 (d,J=17.3 Hz, 1H), 5.17 (d, J=10.9 Hz, 1H), 3.33 (dd, J₁ =18.8 Hz, J₂ =9.7Hz, 1H), 2.92-2.85 (m, 2H), 2.55-2.48 (m, 2H), 1.67-1.49 (m, 4H); ¹³ CNMR (CDCl₃ /DMSO-d₆) δ 197.43, 176.85, 144.67, 141.65, 138.61, 137.09,135.74, 135.06, 128.24, 127.99, 127.87, 126.92, 126.50, 126.39, 125.34,114.21, 40.07, 39.79, 35.30, 31.30, 28.62; MS (FAB-LSIMS) 433 M+H!⁺ ;Elemental Analysis calcd. for C₂₇ H₂₆ O₃.0.5 H₂ O C 79.58, H 6.68; foundC 79.72, H 6.66. ##STR96##

EXAMPLE 56

From 4-bromobenzonitrile: MP 199°-200° C. (dec.); TLC (hexanes--50%ethyl acetate) R_(f) 0.25; ¹ H NMR (CDCl₃ /DMSO-d₆) δ 7.77 (d, J=7.9 Hz,2H), 7.51-7.40 (m, 6H), 6.99-6.86 (m, 5H), 3.20 (dd, J₁ =18.5 Hz, J₂=9.7 Hz, 1H), 2.78-2.71 (m, 2H), 2.37-2.33 (m, 2H), 1.52-1.40 (m, 4H);¹³ C NMR (CDCl₃ /DMSO-d₆) δ 197.03, 176.34, 143.47, 142.63, 141.26,135.75, 131.99, 128.29, 127.65, 127.29, 126.69, 125.03, 117.94, 110.90,39.79, 34.93, 30.91, 28.28; MS (FAB-LSIMS) 398 M+H!⁺ ; HRMS (FAB) calcd.for C₂₆ H₂₄ NO₃ M+H!⁺ 398.17562, Found 398.17703. ##STR97##

EXAMPLE 57

The methyl ester of Example 56 (81 mg, 0.2 mmole, from treatment of anethanol solution of Example 56 with diazomethane followed by solventevaporation in vucuo) was dissolved in 1 mL of toluene and treated withtrimethyltin azide (62 mg, 0.3 mmole). The reaction mixture was refluxedfor 5 days. At this time, the reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, washed with brine and driedover MgSO₄. The crude product was chromatographed with 0-20% methanol inmethylene chloride to afford 56 mg of the methyl ester tetrazoleproduct. The methyl ester product was suspended in ethanol and treatedwith 2N NaOH solution (0.5 mL) and stirred at room temperature for 3hrs. The reaction mixture was then quenched with 2N HCl, diluted withethyl acetate, and the layers were separated. The organic layer waswashed with brine and dried over MgSO₄ to afford 34 mg of Example 57crystallized from ethyl acetate/hexanes.

EXAMPLE 57

MP 176°-177° C.; TLC (methylene chloride--10% methanol) R_(f) 0.11; ¹ HNMR (CDCl₃ /CD₃ OD) δ 8.10 (d, J=8.2 Hz, 2H), 8.01 (d, J=8.5 Hz, 2H),7.74 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.25-7.11 (m, 5H), 3.46(dd, J₁ =18.5 Hz, J₂ =9.9 Hz, 1H), 3.09-2.98 (m, 2H), 2.61-2.59 (m, 2H),1.79-1.61 (m, 4H); ¹³ C NMR (CDCl₃ /CD₃ OD) δ 198.17, 177.69, 144.36,142.36, 141.83, 135.79, 128.66, 128.26, 128.21, 127.94, 127.61, 127.16,125.71, 124.13, 40.36, 39.98, 35.56, 31.54, 28.84; MS (FAB-LSIMS) 441M+H!⁺ ; Elemental Analysis calcd. for C₂₆ H₂₄ N₄ O₃ C 70.89, H 5.49, N12.72; Elemental Analysis found. C 70.81, H 5.44, N 12.41. ##STR98##

EXAMPLE 58

Example 47 (46 mg, 0.094 mmole) was dissolved in 1.5 mL of methylenechloride and treated with trifluoroacetic acid (0.16 mL, 2.06 mmoles).The mixture was stirred at room temperature for 32 hr, when TLC showedcomplete reaction. The solvent was removed at reduced pressure and thesolid obtained was washed with ethyl acetate/hexanes to afford 40 mg ofproduct as TFA salt.

MP 170°-174° C. (dec.); TLC (hexanes--70% ethyl acetate) R_(f) 0.44; ¹ HNMR (CDCl₃ /DMSO-d₆) δ 7.78 (d, J=7.9 Hz, 2H), 7 .41 (d, J=7.9 Hz, 2H),7.30 (m, 3H), 7.08-6.93 (m, 4H), 6.74 (d, J=8.2 Hz, 2H), 3.26 (dd, J₁=18.5 Hz, J₂ =9.7 Hz, 1H), 2.86-2.79 (m, 2H), 2.46-2.38 (m, 2H),1.56-1.44 (m, 4H); ¹³ C NMR (CDCl₃ /DMSO-d₆) δ 197.15, 176.64, 144.75,143.36, 141.45, 134.02, 130.75, 128.05, 127.79, 127.69, 127.52, 125.55,125.14, 116.68, 39.79, 39.61, 35.09, 31.10, 28.44; MS (FAB-LSIMS) 388M+H!⁺ ; Elemental Analysis calcd. for C₂₅ H₂₅ NO₃.TFA C 64.67, H 5.23, N2.79; found. C 64.66, H 5.23, N 2.61. ##STR99##

EXAMPLE 59

This compound was prepared in a similar manner to that of Example 58,except Example 49 was used instead of Example 47.

MP 146°-148° C.; TLC (methylene chloride--10% methanol) R_(f) 0.10; ¹ HNMR (CDCl₃ /DMSO-d₆) δ 8.44 (broad s, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.38(d, J=7.6 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H),7.02-6.82 (m, 5H), 3.85 (s, 2H), 3.20 (dd, J₁ =18.5 Hz, J₂ =9.7 Hz, 1H),2.79-2.72 (m, 2H), 2.39-2.34 (m, 2H), 1.54-1.36 (m, 4H); ¹³ C NMR (CDCl₃/DMSO-d₆) δ 197.20, 176.48, 143.91, 141.29, 139.35, 134.98, 132.85,129.02, 127.99, 127.66, 127.58, 126.85, 126.35, 125.05, 42.16, 34.95,30.94, 30.70, 28.29; MS (FAB-LSIMS) 402 M+H!⁺ ; HRMS (FAB) calcd. forC₂₆ H₂₈ NO₃ M+H!⁺ 402.20692, Found 402.20807. ##STR100##

EXAMPLE 60

The methyl ester of Example 58 (50 mg, 0.13 mmoles) inmethanol/tetrahydrofuran (0.7 mL/0.4 mL) was treated with 37% aqueousformaldehyde (0.11 mL, 1.46 mmoles), glacial acetic acid (0.032 mL), andsodium cyanoborohydride (0.32 mL, 1.0M in THF, 0.32 mmoles). Thereaction mixture was stirred at room temperature for 2 hr at which timethe solvent was removed at reduced pressure and saturated potassiumcarbonate was added to the residue. Ethyl acetate was added to themixture and the layers were separated. The aqueous layers was extractedwith ethyl acetate and the combined extracts were washed with brine,dried over MgSO₄, and the solvent removed at reduced pressure to afford47 mg (88% yield) of the methyl ester product.

TLC (hexanes--20% ethyl acetate) R_(f) 0.35; ¹ H NMR (CDCl₃) δ 7.90 (d,J=8.5 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.25-7.09(m, 5H), 6.74 (d, J=8.5 Hz, 2H), 3.63 (s, 3H), 3.44-3.34 (m, 1H),3.08-2.93 (m, 8H), 2.58 (t, J=7.1 Hz, 2H), 1.72-1.51 (m, 4H).

The methyl ester product (47 mg, 0.11 mmoles) was suspended in ethanol(2 mL) and treated with 10 eq of sodium hydroxide in H₂ O (1 mL). Themixture was stirred at room temperature for 16 hr at which time TLCshowed complete reaction. The ethanol was then removed at reducedpressure, the residue was diluted with ethyl acetate, and the mixturewas acidified with 2N HCl. At this time, the layers were separated andthe organic portion was washed with brine, dried over MgSO₄, and thesolvent removed at reduced pressure to afford 48 mg (96% yield) ofproduct as the hydrochloride salt.

EXAMPLE 60

MP 166°-168° C.; TLC (methylene chloride--5% methanol) R_(f) 0.14; ¹ HNMR (CDCl₃ /DMSO-d₆) δ 7.92 (d, J=8.2 Hz, 2H), 7.59 (broad s, 4H), 7.53(d, J=8.5 Hz, 2H), 7.18-7.05 (m, 5H), 3.38 (m, 1H), 3.08 (s, 6H),2.98-2.88 (m, 2H), 2.56-2.52 (m, 2H), 1.67-1.58 (m, 4H); ¹³ C NMR (CDCl₃/DMSO-d₆) δ 197.45, 176.92, 141.71, 128.58, 128.45, 128.05, 127.95,126.69, 125.42, 119.35, 40.16, 39.84, 35.38, 35.25, 331.36, 28.70; MS(FAB-LSIMS) 416 M+H!⁺ ; HRMS (FAB) calcd. for C₂₇ H₃₀ NO₃ M+H!⁺416.22257, Found 416.22296.

EXAMPLE 61 ##STR101## Steps 1, 2 and 3.

A three neck 2 L flask equipped with a mechanical stirrer was charged,under argon atmosphere, with a potassium tert-butoxide/tert-butanolsolution (800 mL, 1.0M) and brought to reflux. Isobutyraldehyde (66.2mL, 729 mmol) and diethyl succinate (151 mL, 907 mmol) were combined andadded dropwise over 0.5 hours. The reaction solution was refluxed anadditional 1.5 hours and cooled to ambient temperature. The solution wasdiluted with ethyl acetate (800 mL) and washed with 2N hydrochloric acidsolution (500 mL). The ethyl acetate solution was separated and washedwith 10% sodium carbonate solution (6×200 mL). The basic washings werecombined and acidified with concentrated hydrochloric acid. Extractionof product was accomplished with ethyl acetate (5×250 mL). The washingswere combined, dried over magnesium sulfate, and concentrated. A portionof this material was immediately hydrogenated with palladium on carbonusing Parr apparatus. This afforded 90.18 grams of the desired acidester compound shown above. This was then converted to the correspondingester acid chloride by refluxing with oxalyl chloride (1 eq.) ##STR102##Step 4.

A solution of trimethylsilyl tin chloride (21.8 G, 109.5 mmol) infreshly distilled dimethoxyethane (50 mL) was added to a suspension ofsodium (7.6 G, 330 mL), naphthalene (200 mg, 1.56 mmol), anddimethoxyethane under argon atmosphere cooled to -20° C. After 2.5hours, the suspension had turned to a dark green color. The solution wasthen decanted from excess sodium . A solution of 1,4 dibromopyridine (10G, 42.2 mmol) and dimethoxyethane was added over 0.3 hours at 0° C.under argon. The solution was slowly warmed to ambient temperature, thepoured into 500 mL water. The solution was washed with dichloromethane(4×250 mL) and the extracts were combined and dried over magnesiumsulfate. Concentration afforded a brownish solid that was recrystallizedfrom acetonitrile to afford 13.8 G of 1,4 bis-trimethylsilyl tinpyridine. ##STR103## Steps 5, 6 and 7--Preparation of Example 61.

Potassium carbonate (100 mg) was suspended in a solution of the acidchloride from step 3 (1.91 G, 9.6 mmol), the product of step 4 (3.9 G,9.6 mmol) and toluene (50 mL). This was then refluxed 48 hours beforebeing cooled to ambient temperature and diluted with ethyl acetate.Solids were filtered off and solvent removed. The remaining oil waschromatographed on silica with an ethyl acetate/hexane eluent. Theresulting material was coupled to p-iodo ethyl benzene (1 eq.) byrefluxing in a solution of tetrahydrofuran in the presence ofbis-(triphenylphosphine) palladium (II) chloride (20 mole %). Thecoupled product was chromatographed on silica with ethyl acetate/hexaneand saponified by addition of sodium hydroxide to an aqueous/ethanolsolution. Acidification to pH 5 afforded a yellow solid which wasfiltered off and recrystallized from ethyl acetate/hexane. This afforded53 mg of Example 61.

EXAMPLE 61

MP 111°-112° C.; TLC (50% ethyl acetate/hexane) TLC R_(f) =0.44 ¹ H NMR(CDCl₃) δ 8.90(s, 1H); 8.12 (d, J=0.55 Hz, 1H); 8.02 (d, J=7.16 Hz, 1H);7.56 (d, J=6.61 Hz, 2H); 7.35 (d, J=7.99 Hz, 2H); 3.69 (dd, J=18.74 Hzand 9.37 Hz, 1H); 3.40 (dd, J=18.46 Hz and 4.41 Hz, 1H); 3.17 (m, 1H);2.75 (q, J=7.72 Hz, 2H); 1.75 (m, 2H); 1.48 (m, 1H); 1.30 (t, J=7.71 Hz,3H); 0.99 (d, J=6.34 Hz, 3H); 0.93 (d, J=6.34 Hz, 3H); ¹³ C NMR (CDCl₃)δ 200.04, 182.10, 151.97, 147.87, 146.03, 140.72, 135.48, 134.80,129.49, 127.92, 122.70, 120.25, 41.77, 40.65, 38.96, 29.25, 26.47,23.11, 23.05, 16.15; MS (FAB-LSIMS) 340 M+H!⁺, (C₂₁ H₂₅ NO₃, FW=339.44).

EXAMPLE 62, EXAMPLE 63 AND EXAMPLE 64 ##STR104## Step 1(A)

A one-necked, 50-mL, round-bottomed flask equipped with a rubber septumand an argon needle inlet was charged with 7 mL THF, sodium hydride(0.058 g, 2.42 mmol) and cooled to 0° C. while diethyl isobutylmalonate(0.476 g, 0.491 mL, 2.20 mmol) was added dropwise via syringe over ca. 2min. The resulting mixture was stirred for 30 mn at 0° C. and 1 h atroom temperature. The reaction mixture was then cooled to 0° C. while asolution of 2,4'-dibromoacetophenone (0.556 g, 2.00 mmol in 3 mL THF)was added dropwise via cannula over ca. 1 min. The resulting mixture wasstirred for 30 min at 0° C. and 13 h at room temperature. A mixture ofwater (30 mL) and hexanes (50 mL) was added and the resulting aqueousphase was extracted with a second 20-mL portion of hexanes. The combinedorganic phases were dried over MgSO₄, filtered, and concentrated toprovide a yellow oil. Column chromatography on 30 g of silica gel(gradient elution with 1-5% ethyl acetate-hexanes) afforded 0.53 g (64%)of product as a colorless oil:

TLC (5% ethyl acetate-hexanes) R_(f) =0.24; ¹ H NMR (CDCl₃, 300 MHz) δ7.83 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 4.18 (q, J=7.0 Hz, 4H),3.67 (s, 2H), 2.08 (d, J=6.3 Hz, 2H), 1.49-1.61 (m, 1H), 1.22 (t, J=7.0Hz, 6H), and 0.83 (d, J=6.6 Hz, 6H); ¹³ C NMR (CDCl₃, 75 MHz) δ 195.7,171.2, 135.3, 131.9, 129.5, 128.5, 61.5, 55.0, 41.1, 41.0, 24.7, 23.6,and 13.9. ##STR105## Step 1(B)

Treatment of diethyl phenylpropylmalonate (1.00 g, 3.59 mmol) accordingto the general alkylation procedure of step 1(A) afforded 1.11 g (71%)of product as a colorless oil:

TLC (10% ethyl acetate-hexanes) R_(f) =0.19; ¹ H NMR (CDCl₃, 300 MHz) δ7.79 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.07-7.24 (m, 5H) 4.16(q, J=7.0 Hz, 4H), 3.59 (s, 2H), 2.57 (br t, J=7.5 Hz, 2H), 2.11-2.16(m, 2H), 1.49-1.54 (m, 4H), and 1.19 (t, J=7.0 Hz, 6H); ¹³ C NMR (CDCl₃,75 MHz) δ 195.7, 170.7, 141.6, 135.3, 131.9, 129.5, 128.3, 128.2, 125.9,61.5, 55.3, 41.2, 35.8, 32.6, 26.6, and 13.9. ##STR106## Step 2(A)

A one-necked, 10-mL, round-bottomed flask equipped with a refluxcondenser fitted with an argon inlet adapter was charged with 4 mLtoluene, the product of step 1(A) (0.100 g, 0.242 mmol), hexamethylditin (0.159 g, 0.484 mmol), tetrakis(triphenylphoshine)palladium (0.014g, 0.0121 mmol), and heated at reflux for 24 h. The resulting mixturewas concentrated to provide a black oil. Column chromatography on 15 gof silica gel (elution with 5% ethyl acetate-hexanes) afforded 0.107 g(89%) of Compound III as a colorless oil:

TLC (5% ethyl acetate-hexanes) R_(f) =0.33; ¹ H NMR (CDCl₃, 300 MHz) δ7.90 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H), 4.18 (q, J=7.0 Hz, 4H),3.72 (s, 2H), 2.150 (d, J=6.3 Hz, 2H), 1.51-1.60 (m, 1H), 1.22 (t, J=7.0Hz, 6H), 0.83 (d, J=6.6 Hz, 6H), and 0.30 (s, 9H); ¹³ C NMR (CDCl₃, 75MHz) δ 197.0, 171.3, 150.5, 136.0, 126.8, 126.6, 61.4, 54.9, 41.1, 40.9,24.7, 23.6, 13.9, and -9.6. ##STR107## Step 2(B)

Treatment of product from step 1(B) (0.150 g, 0.316 mmol) according tothe general procedure of step 2(A) afforded 0.155 g (88%) of product asa colorless oil:

TLC (10% ethyl acetate-hexanes) R_(f) =0.19; ¹ H NMR (CDCl₃, 300 MHz) δ7.86 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.07-7.24 (m, 5H) 4.16(q, J=7.0 Hz, 4H), 3.64 (s, 2H), 2.56 (br t, J=7.7 Hz, 2H), 2.11-2.18(m, 2H), 1.49-1.54 (m, 4H), 1.19 (t, J=7.0 Hz, 6H), and 0.30 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz) δ 196.9, 170.9, 150.5, 141.7, 136.0, 135.8, 135.8,128.3, 128.3, 125.8, 61.4, 55.3, 41.1, 35.9, 32.6, 26.6, 26.5, 14.0, and-9.6. ##STR108## Step 3(A)

A one-necked, 10-mL, round-bottomed flask equipped with a refluxcondenser fitted with an argon inlet adapter was charged with 1 mLdimethoxyethane or toluene, the product of step 2(A) (0.107 g, 0.215mmol), 1-bromo-3,4-dichlorobenzene (0.097 g, 0.429 mmol),tetrakis(triphenylphosphine)palladium (0.025 g, 0.0216 mmol), and heatedat reflux for 24 h. The resulting mixture was concentrated to provide ablack oil. Column chromatography on 15 g of silica gel (elution with 5%ethyl acetate-hexanes) afforded 0.058 g (57%) of product as a whitesolid:

TLC (10% ethyl acetate-hexanes) R_(f) =0.26; ¹ H NMR (CDCl₃, 300 MHz) δ8.04 (d, J=8.8 Hz, 2H), 7.68 (br s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.52(d, J=8.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 4.19 (q, J=7.0 Hz, 4H), 3.74(s, 2H), 2.11 (d, J=6.6 Hz, 2H), 1.51-1.61 (m, 1H), 1.23 (t, J=7.0 Hz,6H), and 0.85 (d, J=6.6 Hz, 6H); ¹³ C NMR (CDCl₃, 75 MHz) δ 196.2,171.3, 143.3, 139.8, 136.0, 133.2, 132.6, 130.9, 129.1, 128.8, 127.1,126.5, 61.6, 55.0, 41.3, 41.1, 24.8, 23.7, and 14.0. ##STR109## Step3(B)

Reaction of the product of step 2(B) (0.079 g, 0.141 mmol) with4-bromobenzotrifluoride in toluene according to the general couplingprocedure of step 3(A) afforded 0.069 g (91%) of product as a whitesolid:

TLC (10% ethyl acetate-hexanes) R_(f) =0.18; ¹ H NMR (CDCl₃, 300 MHz) δ8.04 (d, J=8.5 Hz, 2H), 7.65-7.71 (m, 6H), 7.08-7.24 (m, 5H), 4.19 (q,J=7.0 Hz, 4H), 3.68 (s, 2H), 2.56 (br t, J=7.7 Hz, 2H), 2.15-2.20 (m,2H), 1.49-1.58 (m, 4H), and 1.21 (t, J=7.0 Hz, 6H);

¹³ C NMR (CDCl₃, 75 MHz) δ 196.1, 170.8, 144.3, 143.3, 141.6, 136.0,130.4, 129.9, 128.7, 128.3, 127.4, 127.2, 125.9, 125.8, 122.3, 61.5,55.4, 41.3, 35.8, 32.7, 26.6, and 13.9. ##STR110## Step 3(C)

Reaction of the product of step 2(B) (0.058 g, 0.104 mmol) with1-bromo-4-nitrobenzene in toluene according to the general couplingprocedure of step 3(A) afforded 0.042 g (78%) of product as a whitesolid:

TLC (10% ethyl acetate-hexanes) R_(f) =0.06; ¹ H NMR (CDCl₃, 300 MHz) δ8.32 (d, J=8.7 Hz, 2H), 8.08 (d, J=8.5 Hz, 2H), 7.76 (d, J=8.5 Hz, 2H),7.71 (d, J=8.7 Hz, 2H), 7.13-7.32 (m, 5H), 4.19 (q, J=7.0 Hz, 4H), 3.68(s, 2H), 2.57 (br t, J=7.7 Hz, 2H), 2.12-2.21 (m, 2H), 1.49-1.62 (m,4H), and 1.20 (t, J=7.0 Hz, 6H); ¹³ C NMR (CDCl₃, 75 MHz) δ 196.0,170.8, 147.6, 146.1, 143.3, 141.6, 136.5, 128.8, 128.3, 128.1, 127.7,127.6, 125.8, 124.2, 61.5, 55.4, 41.4, 35.8, 32.7, 26.6, and 14.0.##STR111## Step 4(B)--Preparation of Example 62

A one-necked, 10-mL, round-bottomed flask equipped with an argon inletadapter was charged with 3 mL ethanol, product of step 3(B) (0.069 g,0.128 mmol), and 1 mL of an aqueous 25% sodium hydroxide solution. Theresulting mixture was stirred for 10 h at room temperature. The reactionmixture was acidified with a 10% HCl solution, and extracted three timeswith 20-mL portions of ether. The organic phase was dried over MgSO₄,filtered, and concentrated to provide a yellow solid, which wasdissolved in 2 mL of 1,4-dioxane and heated to reflux for 24 h in aone-necked, 10-mL, round-bottomed flask equipped with a reflux condenserfitted with an argon inlet adapter. The resulting mixture wasconcentrated to provide a yellow solid. Column chromatography on 10 g ofsilica gel (elution with 40% ethyl acetate-hexanes containing 1% aceticacid) afforded 0.033 g (59%) of Example 62 which was recrystallized oncefrom ethyl acetate-hexanes to provide a white solid.

MP 165° C.; TLC (10% methanol-methylene chloride) R_(f) =0.50; HPLC (10%methanol-methylene chloride) t_(R) =7.6 min; ¹ H NMR (CDCl₃, 300 MHz) δ8.04 (d, J=8.5 Hz, 2H), 7.65-7.71 (m, 6H), 7.14-7.29 (m, 5H), 3.47 (dd,J=8.1, 16.9 Hz, 1H), 3.03-3.16 (m, 2H), 2.65 (brt, J=7.0 Hz, 2H), and1.66-1.80 (m, 4H); ¹³ C NMR (CDCl₃, 75 MHz) δ 197.4, 180.8, 144.4,143.3, 141.7, 135.9, 130.1, 128.8, 128.4, 128.3, 127.6, 127.5, 126.8,125.9, 122.2, 40.2, 39.9, 35.6, 31.4, and 28.9; FAB-LCIMS: 441 M+H!⁺ ;HRMS: calcd. for C₂₆ H₂₃ F₃ O₃ +H!⁺ : 441.16775; found: 441.16559.##STR112## Step 4(C)--Preparation of Example 63:

Treatment of the product of step 3(C) (0.042 g, 0.081 mmol) according tothe general procedure of Example 62 afforded 0.023 g (68%) of Example 63which was recrystallized once from ethyl acetate-hexanes to provide awhite solid.

MP 183° C.; TLC (10% methanol-methylene chloride) R_(f) =0.50; HPLC(gradient elution 0.5-2.5% methanol-methylene chloride containing 0.1%TFA) t_(R) =13.7 min; ¹ H NMR (CDCl₃, 300 MHz) δ 8.32 (d, J=8.7 Hz, 2H),8.07 (d, J=8.5 Hz, 2H), 7.76 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H),7.13-7.32 (m, 5H), 3.47 (dd, J=8.1, 16.9 Hz, 1H), 3.01-3.12 (m, 2H),2.64 (brt, J=7.0 Hz, 2H), and 1.66-1.80 (m, 4H); FAB-LCIMS: 418 M+H!⁺ ;HRMS: calcd. for C₂₅ H₂₃ NO₅ +H!⁺ : 418.16545; found: 418.16620.##STR113## Step 4(A)--Preparation of Example 64:

Treatment of the product of step 3(A) (0.050 g, 0.104 mmol) according tothe general procedure of Example 62 afforded 0.010 g (25%) of Example 64which was recrystallized once from ethyl acetate-hexanes to provide awhite solid.

MP 132° C.; TLC (10% methanol-methylene chloride) R_(f) =0.49; HPLC(gradient elution 0.5-2.5% methanol-methylene chloride containing 0.1%TFA) t_(R) =12.7 min; ¹ H NMR (CDCl₃, 300 MHz) δ 8.02 (d, J=8.5 Hz, 2H),7.68 (s, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.42 (d,J=8.1 Hz, 2H), 3.43 (dd, J=8.1, 16.9 Hz, 1H), 3.03-3.16 (m, 2H),1.63-1.73 (m, 2H), 1.38-1.43 (m, 1H), 0.97 (d, J=6.3 Hz, 3H), and 0.91(d, J=6.3 Hz, 3H); FAB-LCIMS: 379 M+H!⁺ ; HRMS: calcd. for C₂₀ H₂₀ Cl₂O₃ +H!⁺ : 379.08678; found: 379.08682. ##STR114## Step 1

Treatment of the product of step 1(B) of the Example 62 preparation(13.34 g, 28.06 mmol) according to the general procedure of Example 62,step 4(B) afforded 4.36 g (41%) of the above 4-bromophenyl intermediatewhich was recrystallized once from 1-chlorobutane to provide a whitesolid.

MP 147° C.; TLC (30% ethyl acetate-hexanes containing 1% acetic acid)R_(f) =0.29; ¹ H NMR (CDCl₃, 300 MHz) δ 7.79 (d, J=8.5 Hz, 2H), 7.58 (d,J=8.5 Hz, 2H), 7.14-7.28 (m, 5H), 3.38 (dd, J=8.8, 17.7 Hz, 1H),3.06-3.10 (m, 1H), 2.97 (dd, J=4.4, 17.7 Hz, 1H), 2.63 (brt, J=7.0 Hz,2H), and 1.61-1.81 (m, 4H); ¹³ C NMR (CDCl₃, 75 MHz) δ 196.9, 180.8,141.7, 135.1, 131.9, 129.6, 128.5, 128.4, 125.9, 40.0, 39.8, 35.6, 31.4,and 28.8. ##STR115## Step 2

Treatment of the 4-bromophenyl intermediate from step 1 (1.00 g, 2.66mmol) in the presence of anhydrous K₂ CO₃, according to the generalprocedure of step 2(A) of the example 64 preparation afforded 0.706 g(58%) of the 4-trimethylstannylphenyl compound as a white solid:

TLC (30% ethyl acetate-hexanes containing 1% acetic acid) R_(f) =0.47;HPLC (gradient elution 0.5-2.5% methanol-methylene chloride containing0.1% TFA) t_(R) =11.4 min; ¹ H NMR (CDCl₃, 300 MHz) δ 7.86 (d, J=8.1 Hz,2H), 7.58 (d, J=8.1 Hz, 2H), 7.07-7.25 (m, 5H), 3.41 (dd, J=8.1, 17.1Hz, 1H), 3.00-3.16 (m, 2H), 2.63 (brt, J=7.0 Hz, 2H), 1.66-1.80 (m, 4H),and 0.30 (s, 9H). ##STR116## Step 3--Preparation of Example 65

A one-necked, 10-mL, round-bottomed flask equipped with a refluxcondenser fitted with an argon inlet adapter was charged with 3 mLtoluene, the product of step 2 (0.050 g, 0.108 mmol),1-bromo-3,4-dichlorobenzene (0.049 g, 0.217 mmol), andtetrakis(triphenylphoshine)palladium (0.013 g, 0.0112 mmol). Theresulting mixture was heated at reflux for 24 h, and then concentratedto provide a black oil. Column chromatography on 15 g of silica gel(elution with 20% ethyl acetate-hexanes containing 0.5% acetic acid)afforded 0.033 g (69%) of Example 65 which was recrystallized once fromethyl acetate-hexanes to provide a white solid.

MP 137° C.; TLC (elution with 30% ethyl acetate-hexanes containing 1%acetic acid) R_(f) =0.34; HPLC (gradient elution 0.5-2.5%methanol-methylene chloride containing 0.1% TFA) t_(R) =11.7 min; ¹ HNMR (CDCl₃, 300 MHz) δ 8.01 (d, J=8.1 Hz, 2H), 7.68 (br s, 1H), 7.61 (d,J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.13-7.32(m, 5H), 3.46 (dd, J=8.1, 16.5 Hz, 1H), 3.03-3.15 (m, 2H), 2.65 (brt,J=7.0 Hz, 2H), and 1.66-1.80 (m, 4H). ##STR117##

EXAMPLE 66

Reaction of the product of step 2 from example 65 (0.100 g, 0.218 mmol)with 1-bromo-3,5-dichlorobenzene in toluene according to the generalcoupling procedure of Example 65 afforded 0.044 g (46%) of Example 66which was recrystallized once from 1-chlorobutane to provide a whitesolid.

MP 123° C.; TLC (elution with 30% ethyl acetate-hexanes containing 1%acetic acid) R_(f) =0.39; HPLC (elution 0.5% methanol-methylene chloridecontaining 0.01% TFA) t_(R) =11.0 min; ¹ H NMR (CDCl₃, 300 MHz) δ 8.01(d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.46 (br s, 2H), 7.37 (br s,1H), 7.42 (d, J=8.1 Hz, 2H), 7.15-7.29 (m, 5H), 3.46 (dd, J=8.1, 16.9Hz, 1H), 3.02-3.14 (m, 2H), 2.65 (brt, J=7.0 Hz, 2H), and 1.66-1.82 (m,4H); FAB-LCIMS: 442 M+H!⁺.

EXAMPLE 67 ##STR118## Step 1--Preparation of 1-Acetoxy-4-bromobenzene:

A one-necked, 25-mL, round-bottomed flask equipped with an argon inletadapter was charged with 5 mL pyridine, 4-bromophenol (1.00 g, 5.78mmol), and acetic anhydride (2.80 g, 27.4 mmol). The resulting mixturewas stirred for 12 h at room temperature. A mixture of water (20 mL) andether (50 mL) was added and the resulting organic phase was washed witha second 20-mL portion of water. The organic phase was dried over MgSO₄,filtered, and concentrated to provide a colorless oil:

TLC (10% ethyl acetate-hexanes)R_(f) =0.54; ¹ H NMR (CDCl₃, 300 MHz) δ7.35 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), and 2.16 (s, 3H).##STR119## Step 2--Preparation of Example 67:

Reaction of the product of step 2 from example 65 (0.100 g, 0.218 mmol)with 1-acetoxy-4-bromobenzene in toluene according to the generalcoupling procedure of Example 65 afforded, after HPLC purification,0.021 g (22%) of Example 67 as a solid.

MP 131° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.35; ¹ H NMR (CDCl₃, 300 MHz) δ 8.00 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.13-7.29 (m, 7H), 3.46 (dd, J=8.1,16.9 Hz, 1H), 3.03-3.13 (m, 2H), 2.64 (brt, J=7.0 Hz, 2H), 2.32 (s, 3H),and 1.65-1.78 (m, 4H); FAB-LCIMS: 431 M+H!⁺. ##STR120##

EXAMPLE 68

Reaction of the product of step 2 from example 65 (0.100 g, 0.218 mmol)with 2-bromo-5-chlorothiophene in toluene according to the generalcoupling procedure of Example 65 afforded, after HPLC purification,0.016 g (18%) of Example 68 as a solid.

MP 120° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.24; ¹ H NMR (CDCl₃, 300 MHz) δ 7.93 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5Hz, 2H), 7.14-7.28 (m, 6H), 6.92 (d, J=3.7 Hz, 1H), 3.42 (dd, J=8.1,16.9 Hz, 1H), 3.00-3.13 (m, 2H), 2.64 (brt, J=7.0 Hz, 2H), and1.680-1.78 (m, 4H); FAB-LCIMS: 413 M+H!⁺. ##STR121## Preparation of4-Ethoxybenzeneboronic Acid

A one-necked, 25-mL, round-bottomed flask equipped with a refluxcondenser fitted with an argon inlet adapter was charged with magnesiumpowder (0.255 g, 10.5 mmol, -50 mesh), 7 mL THF, and 4-bromophenetol(1.41 g, 1.00 mL, 7.00 mmol). The resulting mixture was heated to refluxfor 3 h. A second one-necked, 25-mL, round-bottomed flask equipped witha rubber septum and an argon inlet needle was charged with triisopropylborate (3.95 g, 4.85 mL, 21.00 mmol) and cooled to -78° C. while theGrignard reagent prepared above was added dropwise via cannula over ca.5 min. The cooling bath was removed and the reaction mixture was stirredfor 3 h at 30 room temperature. A mixture of ether (50 mL) and a 10% HClsolution (50 mL) was added and the resulting organic phase was washedwith a 100-mL portion of water. The organic phase was dried over MgSO₄ ;filtered, and concentrated to provide a yellow solid which wasrecrystallized from ether-hexanes to provide 0.783 g (67%) of a whitesolid:

¹ H NMR (CDCl₃, 300 MHz) δ 8.14 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz,2H), 4.11 (q, J=7.0 Hz, 2H), and 1.45 (t, J=7.0 Hz, 3H). ##STR122##

EXAMPLE 69

A one-necked, 100-mL, round-bottomed flask equipped with a refluxcondenser fitted with an argon inlet adapter was charged with 30 mLtoluene, the product of step 1 of the example 65 preparation (1.00 g,2.66 mmol), 4-methoxybenzeneboronic acid (1.60 g, 10.5 mmol), sodiumcarbonate or potassium carbonate (1.60 g, 11.6 mmol) andtetrakis(triphenyl-phoshine)palladium (0.300 g, 0.260 mmol). Theresulting mixture was heated at reflux for 12 h. After cooling to roomtemperature, 5 mL of 30% hydrogen peroxide solution was added and theresulting mixture stirred for 1 h. A mixture of ether (300 mL) and a 10%HCl solution (300 mL) was added and the resulting organic phase waswashed with 300 mL of saturated sodium chloride solution. The organicphase was dried over MgSO₄, filtered, and concentrated to afford 0.879 g(82%) of Example 69 which was recrystallized once from 1-chlorobutane toprovide a white solid.

MP 169° C.; TLC (elution with 2% methanol-methylene chloride) R_(f)=0.19; ¹ H NMR (CDCl₃, 300 MHz) δ 8.01 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.5Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.17-7.33 (m, 5H), 7.01 (d, J=8.8 Hz,2H), 3.87 (s, 3H), 3.48 (dd, J=8.1, 16.5 Hz, 1H), 3.03-316 (m, 2H), 2.67(brt, J=7.0 Hz, 2H), and 1.71-1.81 (m, 4H); FAB-LCIMS: 403 M+H!⁺.##STR123##

EXAMPLE 70

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with 3-chloro-4-fluorobenzeneboronic acid in tolueneaccording to the general boronic acid coupling procedure of Example 69afforded 0.036 g (32%) of Example 69 which was recrystallized once from1-chlorobutane to provide a white solid.

MP 141° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.27; HPLC (elution 0.5% methanol-methylene chloride containing 0.01%TFA)t_(R) =12.2 min; ¹ H NMR (CDCl₃, 300 MHz) δ 8.00 (d, J=8.1 Hz, 2H),7.58-7.66 (m, 3H), 7.42-7.48 (m, 1H), 7.15-7.29 (m, 6H), 3.46 (dd,J=8.1, 16.5 Hz, 1H), 3.02-3.14 (m, 2H), 2.65 (brt, J=7.0 Hz, 2H), and1.64-1.84 (m, 4H); FAB-LCIMS: 425 M+H!⁺. ##STR124##

EXAMPLE 71

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with 4-ethoxybenzeneboronic acid in toluene according tothe general boronic acid coupling procedure of Example 69 afforded 0.011g (10%) of Example 71 which was recrystallized once from ethylacetate-hexanes to provide a white solid.

MP 144° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.26; HPLC (elution 0.5% methanol-methylene chloride containing 0.01%TFA)t_(R) =14.5 min; ¹ H NMR (CDCl₃, 300 MHz) δ 7.98 (d, J=8.1 Hz, 2H),7.62 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.15-7.26 (m, 5H), 6.99(d, J=8.5 Hz, 2H), 4.07 (q, J=7.0 Hz, 2H), 3.45 (dd, J=8.1, 16.5 Hz,1H), 3.06-3.13 (m, 2H), 2.64 (brt, J=7.0 Hz, 2H), 1.69-1.83 (m, 4H), and1.43 (t, J=7.0 Hz, 3H). ##STR125##

EXAMPLE 72

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with thiophene-3-boronic acid in toluene according to thegeneral boronic acid coupling procedure of Example 69 and bypassing thehydrogen peroxide work-up afforded, after HPLC purification, 0.027 g(27%) of Example 72 as a solid.

MP 145° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.29; HPLC (elution 0.5% methanol-methylene chloride containing 0.01%TFA)t_(R) =13.7 min; ¹ H NMR (CDCl₃, 300 MHz) δ 7.97 (d, J=8.8 Hz, 2H),7.66 (d, J=8.8 Hz, 2H), 7.56-7.59 (m, 1H), 7.41-7.45 (m, 2H), 7.13-7.30(m, 5H), 3.44 (dd, J=8.1, 16.5 Hz, 1H), 3.04-3.13 (m, 2H), 2.64 (brt,J=7.0 Hz, 2H), and 1.73-1.79 (m, 4H); FAB-LCIMS: 379 M+H!⁺. ##STR126##

EXAMPLE 73

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with 2,4-dichlorobenzeneboronic acid in toluene accordingto the general boronic acid coupling procedure of Example 69 afforded,after HPLC purification, 0.031 g (26%) of Example 73 as a white solid.

MP 138° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.32; ¹ H NMR (CDCl₃, 300 MHz) δ 7.97 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8Hz, 2H), 7.56-7.59 (m, 1H), 7.41-7.45 (m, 2H), 7.13-7.30 (m, 5H), 3.44(dd, J=8.1, 16.5 Hz, 1H), 3.04-3.13 (m, 2H), 2.64 (brt, J=7.0 Hz, 2H),and 1.73-1.79 (m, 4H); ¹³ C NMR (CDCl₃, 75 MHz) δ 197.5, 180.6, 143.2,141.8, 135.7, 132.8, 131.8, 129.9, 129.7, 128.4, 128.1, 127.8, 127.3,125.6, 40.2, 39.8, 35.6, 31.4, and 28.9; FAB-LCIMS: 441 M+H!⁺.##STR127##

EXAMPLE 74

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with 4-formylbenzeneboronic acid in toluene according tothe general boronic acid coupling procedure of Example 69 afforded,after HPLC purification, 0.007 g (7%) of Example 74 as a white solid.

MP 174° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.26; ¹ H NMR (CDCl₃, 300 MHz) δ 10.06 (s, 1H), 8.05 (d, J=8.5 Hz, 2H),7.97 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H),7.14-7.30 (m, 5H), 3.48 (dd, J=8.1, 16.5 Hz, 1H), 3.07-3.13 (m, 2H),2.65 (brt, J=7.0 Hz, 2H), and 1.69-1.83 (m, 4H). ##STR128##

EXAMPLE 75

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with 3,5-bis(trifluoromethyl)benzene-boronic acid intoluene according to the general boronic acid coupling procedure ofExample 69 using Na2CO₃ afforded, after HPLC purification, 0.004 g (7%)of Example 75 as a white solid.

MP 145° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.35; HPLC (elution 0.5% methanol-methylene chloride containing 0.01%TFA)t_(R) =13.4 min; ¹ H NMR (CDCl₃, 300 MHz) δ 8.07 (d, J=8.8 Hz, 2H),8.02 (s, 2H), 7.90 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.15-7.29 (m, 5H),3.48 (dd, J=8.1, 16.5 Hz, 1H), 3.04-3.12 (m, 2H), 2.65 (brt, J=7.0 Hz,4H), and 1.70-1.78 (m, 2H); FAB-LCIMS: 509 M+H!⁺. ##STR129##

EXAMPLE 76

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with thiophene-2-boronic acid in toluene according to thegeneral boronic acid coupling procedure of Example 69 using Na₂ CO₃ andbypassing the hydrogen peroxide work-up afforded, after HPLCpurification, 0.0015 g (2%) of Example 76 as a solid.

TLC (elution with 5% methanol-methylene chloride) R_(f) =0.27; ¹ H NMR(CDCl₃, 300 MHz) δ 7.94 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.41(br d, J=3.7 Hz, 1H), 7.36 (br d, J=5.2 Hz, 1H), 7.09-7.28 (m, 6H), 3.43(dd, J=8.1, 16.5 Hz, 1H), 3.03-3.12 (m, 2H), 2.64 (brt, J=7.0 Hz, 2H),and 1.69-1.78 (m, 4H). ##STR130##

EXAMPLE 77

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with 3-trifluoromethylbenzeneboronic acid in tolueneaccording to the general boronic acid coupling procedure of Example 69using Na₂ CO₃ afforded, after HPLC purification, 0.027 g (23%) ofExample 77 as a white solid.

MP 118° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.17; HPLC (elution 0.5% methanol-methylene chloride containing 0.1%TFA)t_(R) =7.4 min; ¹ H NMR (CDCl₃, 300 MHz) δ 8.04 (d, J=8.5 Hz, 2H),7.84 (s, 1H), 7.58-7.68 (m, 4H), 7.16-7.29 (m, 5H), 3.47 (dd, J=8.1,16.5 Hz, 1H), 3.05-3.11 (m, 2H), 2.65 (brt, J=7.0 Hz, 2H), and 1.70-1.79(m, 4H); FAB-LCIMS: 441 M+H!⁺. ##STR131##

EXAMPLE 78

Reaction of the product of step 1 of the example 65 preparation (0.100g, 0.266 mmol) with 2-formylbenzeneboronic acid in toluene according tothe general boronic acid coupling procedure of Example 69 afforded,after HPLC purification, 0.003 g (3%) of Example 78 as a white solid.

TLC (elution with 5% methanol-methylene chloride) R_(f) =0.23; ¹ H NMR(CDCl₃, 300 MHz) δ 9.94 (s, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.49-7.66 (m,3H), 7.47 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.14-7.30 (m, 5H),3.49 (dd, J=8.1, 16.5 Hz, 1 H), 3.05-3.13 (m, 2H), 2.66 (brt, J=7.0 Hz,2H), and 1.71-1.80 (m, 4H). ##STR132##

EXAMPLE 79

A one-necked, 100-mL, round-bottomed flask equipped with a refluxcondenser was charged with 35 mL acetic acid, Example 69 (0.751 g, 1.86mmol), and 20 mL 48% hydrobromic acid. The resulting mixture was heatedat 90° C. for 12 h. After cooling to room temperature, 100 mL of ethylacetate was added and the resulting mixture was washed twice with 100 mLof water, and once with 100 mL saturated sodium chloride solution. Theorganic phase was dried over MgSO₄, filtered, and concentrated to afforda brown solid. Column chromatography on 50 g of silica gel (5%methanol-methylene chloride) afforded 0.530 g (73%) of Example 69 as awhite solid.

MP 189° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.28; HPLC (elution 0.5% methanol-methylene chloride containing 0.01%TFA)t_(R) =15.2 min; ¹ H NMR (DMSO-d₆, 300 MHz) δ 7.99 (d, J=8.5 Hz,2H), 7.72 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 7.16-7.27 (m, 5H),6.87 (d, J=8.5 Hz, 2H), 3.33 (dd, J=8.1, 16.5 Hz, 1H), 3.03-3.16 (m,2H), 2.59 (brt, J=7.0 Hz, 2H), and 1.60-1.71 (m, 4H). ##STR133##

EXAMPLE 80

A one-necked, 10-mL, round-bottomed flask equipped with a rubber septumand an argon needle inlet was charged with 1 mL DMF and Example 79(0.100 g, 0.257 mmol). Sodium hydride (0.014 g, 0.583 mmol) was addedand the reaction mixture stirred 10 min at room temperature.1-lodopropane (0.130 g, 0.075 mL, 0.765 mmol) was added and theresulting mixture heated to 60° C. for 12 h. After cooling to roomtemperature, the reaction mixture was diluted with 50 mL of ethylacetate, washed twice with 20 mL of water, and washed once with 20 mLsaturated sodium chloride solution. The organic phase was dried overMgSO₄, filtered, and concentrated to afford an oil. A second,one-necked, 10-mL, round-bottomed flask equipped with a rubber septumand an argon needle inlet was charged with the above oil, 1 mL THF, 1 mLmethanol, and 2 mL of a 1M sodium hydroxide solution. The resultingmixture was stirred 10 min at room temperature, dissolved in 20 mL ethylacetate and washed twice with 20 mL of a 10% HCL solution. The organicphase was dried over Mg₂ SO₄, filtered, and concentrated to afford,after HPLC purification, 0.014 g (13%) of Example 80 as a white solid.

MP 126° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.31; ¹ H NMR (CDCl₃, 300 MHz) δ 7.98 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.13-7.29 (m, 5H), 6.97 (d, J=8.8 Hz,2H), 3.96 (t, J=6.6 Hz, 2H), 3.45 (dd, J=8.1, 16.5 Hz, 1H), 3.03-3.12(m, 2H), 2.64 (brt, J=7.0 Hz, 2H), 1.67-1.86 (m, 6H), and 1.04 (t, J=7.4Hz, 3H). ##STR134##

EXAMPLE 81

Reaction of Example 79 (0.100 g, 0.257 mmol) with 1-iodopentaneaccording to the general alkylation procedure of Example 80 afforded,after HPLC purification, 0.024 g (20%) of Example 81 as a white solid:

MP 110° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.32; ¹ H NMR (CDCl₃, 300 MHz) δ 7.98 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.15-7.28 (m, 5H), 6.97 (d, J=8.8 Hz,2H), 3.99 (t, J=6.6 Hz, 2H), 3.44 (dd, J=8.1, 16.5 Hz, 1H), 3.04-3.12(m, 2H), 2.64 (brt, J=7.0 Hz, 2H), 1.69-1.83 (m, 6H), 1.37-1.47 (m, 4H),and 0.93 (t, J=7.0 Hz, 3H); FAB-LCIMS: 459 M+H!⁺. ##STR135##

EXAMPLE 82

Reaction of Example 79 (0.079 g, 0.203 mmol) with 1-iodohexane accordingto the general alkylation procedure afforded, after radialchromatography on silica gel (methanol-methylene chloride), 0.055 g(58%) of Example 82 as a white solid.

MP 110° C.; TLC (elution with 5% methanol-methylene chloride) R_(f)=0.24; HPLC (elution 4% methanol-methylene chloride containing 0.01%TFA)t_(R) =5.4 min; ¹ H NMR (CDCl₃, 300 MHz) δ 7.98 (d, J=8.8 Hz, 2H),7.62 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.15-7.30 (m, 5H), 6.97(d, J=8.8 Hz, 2H), 3.99 (t, J=6.6 Hz, 2H), 3.45 (dd, J=8.1, 16.5 Hz,1H), 3.07-3.13 (m, 2H), 2.65 (brt, J=7.0 Hz, 2H), 1.70-1.84 (m, 6H),1.32-1.49 (m, 6H), and 0.89 (t, J=7.0 Hz, 3H); FAB-LCIMS: 473 M+H!⁺.##STR136##

EXAMPLE 83

Reaction of Example 79 (0.100 g, 0.257 mmol) with 1-iodobutane accordingto the general alkylation procedure afforded, after HPLC purification,0.054 g (47%) of Example 83 as a white solid.

MP 116° C.; TLC (elution with 30% ethyl acetate-hexanes containing 1%acetic acid) R_(f) =0.56; HPLC (elution 4% methanol-methylene chloridecontaining 0.01% TFA)t_(R) =6.3 min; ¹ H NMR (CDCl₃, 300 MHz) δ 7.98 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.15-7.30(m, 5H), 6.97 (d, J=8.8 Hz, 2H), 4.00 (t, J=6.6 Hz, 2H), 3.44 (dd,J=8.1, 16.5 Hz, 1H), 3.04-3.12 (m, 2H), 2.65 (brt, J=7.0 Hz, 2H),1.69-1.83 (m, 6H), 1.46-1.53 (m, 2H), and 0.97 (t, J=7.0 Hz, 3H);FAB-LCIMS: 445 M+H!⁺. ##STR137##

EXAMPLE 84

Reaction of Example 79 (0.102 g, 0.263 mmol) with 1-iodo-3-phenylpropaneaccording to the general alkylation procedure afforded, after radialchromatography on silica gel (methanol-methylene chloride), 0.022 g(17%) of Example 84 as a white solid.

MP 159° C.; TLC (elution with 30% ethyl acetate-hexanes containing 1%acetic acid) R_(f) =0.64; HPLC (elution 4% methanol-methylene chloridecontaining 0.01% TFA)t_(R) =6.0 min; ¹ H NMR (CDCl₃, 300 MHz) δ 7.98 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.14-7.37(m, 10H), 6.96 (d, J=8.8 Hz, 2H), 4.00 (t, J=6.6 Hz, 2H), 3.45 (dd,J=8.1, 16.5 Hz, 1H), 3.06-3.15 (m, 2H), 2.82 (brt, J=7.4 Hz, 2H), 2.65(brt, J=7.0 Hz, 2H), 2.13-2.17 (m, 2H), and 1.69-1.84 (m, 4H);FAB-LCIMS: 507 M+H!⁺. ##STR138##

EXAMPLE 85

Reaction of Example 79 (0.104 g, 0.267 mmol) with 2-iodopropaneaccording to the general alkylation procedure afforded, after radialchromatography on silica gel (methanol-methylene chloride), 0.088 g(77%) of Example 85 as a white solid.

MP 122° C.; TLC (elution with 30% ethyl acetate-hexanes containing 1%acetic acid) R_(f) =0.66; HPLC (elution 4% methanol-methylene chloridecontaining 0.01% TFA)t_(R) =7.1 min; ¹ H NMR (CDCl₃, 300 MHz) δ 7.98 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.15-7.28(m, 5H), 6.96 (d, J=8.8 Hz, 2H), 4.59 (sept, J=5.9 Hz, 1H), 3.44 (dd,J=8.1, 16.5 Hz, 1H), 3.04-3.12 (m, 2H), 2.64 (brt, J=7.0 Hz, 2H),1.69-1.83 (m, 4H), and 1.35 (d, J=5.9 Hz, 6H); FAB-LCIMS: 431 M+H!⁺.##STR139##

EXAMPLE 86

Reaction of Example 79 (0.102 g, 0.263 mmol) with 1-iodoheptaneaccording to the general alkylation procedure afforded, after radialchromatography on silica gel (methanol-methylene chloride), 0.037 g(29%) of Example 86 as a white solid.

MP 114° C.; TLC (elution with 30% ethyl acetate-hexanes containing 1%acetic acid) R_(f) =0.61; HPLC (elution 4% methanol-methylene chloridecontaining 0.01% TFA)t_(R) =5.8 min; ¹ H NMR (CDCl₃, 300 MHz) δ 7.98 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.17-7.30(m, 5H), 6.97 (d, J=8.8 Hz, 2H), 3.99 (t, J=6.6 Hz, 2H), 3.44 (dd,J=8.1, 16.5 Hz, 1H), 3.04-3.12 (m, 2H), 2.65 (brt, J=7.0 Hz, 2H),1.69-1.83 (m, 6H), 1.37-1.47 (m, 8H), and 0.89 (t, J=7.0 Hz, 3H);FAB-LCIMS: 487 M+H!⁺.

EXAMPLE 87 ##STR140## Step 1--Preparation of Ethyl2-carboethoxy-5-phenyl-pentanoate:

A dry 2-L, three-necked, round-bottomed flask was equipped with a stirbar, a pressure equalizing addition funnel, an argon inlet and athermometer. The flask was charged with a suspension of sodium hydride(8.4 g of 95% NaH; .sub.˜ 0.33 mol) in dry THF (700 mL) and was cooledwith an ice water bath. Diethyl malonate (48.54 g, 0.30 mol) was addeddropwise from the addition funnel over 25 min. Stirring was continuedfor 1.5 hr before adding 1-bromo-3-phenylpropane (47 mL, .sub.˜ 61 g,.sub.˜ 0.30 mol) over 10 min via the addition funnel. Rinses of theaddition funnel (THF, 2×10 mL) were added to the reaction mixture andstirring was continued for 30 min. The addition funnel and thermometerwere replaced with a reflux condenser and stopper, and the reaction washeated at reflux for 19 hr. The mixture was cooled to room temperatureand then with an ice water bath. Distilled water (400 mL) was slowlyadded with stirring. The layers were separated and the aqueous phase wasextracted with chloroform (100 mL). The combined organics were washedwith 10% HCl (250 mL) and the separated aqueous phase was back-extractedwith chloroform (100 mL). The combined organics were washed withsaturated NaHCO₃ (250 mL) and the separated aqueous phase wasback-extracted with chloroform (100 mL). The organics were dried (Na₂SO₄) and concentrated to yield a yellow oil which was purified bydistillation through a Vigreux column at reduced pressure (0.4 torr).The fraction boiling at 124°-138° C. was clean desired product 20 (57.21g, 0.206 mol; 68% yield).

TLC (hexanes-dichloromethane, 1:1): R_(f) =0.32; ¹ H-NMR (DMSO-d₆): δ1.13 (t, J=7.0 Hz, 6H), 1.50-1.58 (m, 2H), 1.70-1.78 (m, 2H), 2.56 (t,J=7.4 Hz, 2H), 3.46 (t, J=7.4 Hz, 2H), 4.08 (q, J=7.0 Hz, 2H), 7.12-7.16(m, 3H), 7.22-7.27 (m, 2H). ##STR141## Step 2--Preparation of1-(2-Bromoethanone)-4-(4-chloro-phenyl)-benzene:

A 2-L, three-necked, round-bottomed flask was equipped with a mechanicalstirrer, a thermometer and an argon inlet. The flask was charged with asolution of 4-chlorobiphenyl (48.30 g, 0.256 mol) in dichloromethane(500 mL, freshly opened bottle). Bromoacetyl bromide (23 mL, ˜53.3 g,˜0.26 mol) was added via syringe and the solution was cooled with an icewater bath to an internal temperature of 3° C. The thermometer wastemporarily removed and AlCl₃ was added portionwise over 5 min. Theinternal temperature rose to 10° C. and white gas evolved from theopaque olive green reaction mixture. After 24 h of stirring, thereaction was quenched by cautiously pouring into cold 10% HCl (1 L). Theorganic layer became cloudy yellow green. Chloroform was added to helpdissolve solids, but the organic layer never became transparent. Theorganics were concentrated on a rotary evaporator and were dried furtherunder high vacuum. The crude product was a pale green solid (˜82 g)which recrystallized from hot ethyl acetate to give the desired compound21 as brown needles (58.16 g). Concentration of the mother liquorfollowed by addition of hexanes delivered a second crop of crystals(11.06 g) which gave an NMR spectrum identical to that of the firstcrop. The total yield of the title product was 87%.

TLC (hexanes-dichloromethane, 2:1): R_(f) =0.30; ¹ H-NMR (CDCl3): δ 4.48(s, 2H), 7.45 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.5,2H), 8.06 (d, J=8.7, 2H). ##STR142## Step 3--Preparation of2-Carboxy-5-phenyl-2- 2-oxo-2-(4'-chloro-4-biphenyl)ethyl!-pentanoicacid:

A dry 1-L, three-necked, round-bottomed flask was equipped with amagnetic stir bar, a thermometer, an argon inlet and a pressureequalizing addition funnel. The flask was charged with a suspension ofsodium hydride (4.7 g of 95% NaH; ˜0.185 mol) in dry THF (400 mL), andthe addition funnel was charged with the malonate product from step 1(46.76 g, 0.168 mol). The reaction vessel was cooled with an ice waterbath while the malonate was added dropwise over 18 min. After thereaction stirred for 45 min, a solution of the bromomethyl ketoneproduct from step 2 (52.00 g, 0.168 mol) in dry THF (200 mL) was addedvia the addition funnel over 20 min. The deep orange reaction mixturewas stirred under argon overnight while slowly warming to roomtemperature. The reaction vessel was cooled in an ice water bath whiledistilled water (300 mL) was added cautiously. The layers were separatedand the aqueous phase was extracted with dichloromethane (100 mL). Thecombined organics were washed sequentially with 10% HCl and saturatedsodium bicarbonate (200 mL). The combined aqueous washes wereback-extracted with dichloromethane (50 mL). The combined organics weredried (Na₂ SO₄) and concentrated to afford a dark orange oil (84.07 g).This crude material was used in the next step without purification.

A portion of the crude oil (24.09 g, ˜47.5 mmol) was taken up in ethanol(400 mL; the sample did not completely dissolve). To this mixture wasadded NaOH solution (19.0 g of 50 wt. % aqueous NaOH, ˜238 mmol) and thereaction was stirred under argon overnight at room temperature. After 20h of stirring, the reaction showed no diester remaining by TLC. Themixture was brought to pH ˜1 by adding concentrated HCl (˜20 mL) and wasthen concentrated to dryness. An attempt to partition this materialbetween chloroform (200 mL) and water (100 mL) failed to dissolve allsolids. Collection of the undissolved solid followed by drying underhigh vacuum gave clean desired (12.38 g, 27.46 mmol). Examination of theaqueous and organic phases by TLC showed a negligible amount of desired.The saponification procedure was repeated on the remaining crude diester(59.47 g, ˜117 mol) to deliver additional diacid (28.34 g, 62.85 mmol).The total yield for the alkylation-saponification process to yield thediacid productwas 54%.

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)=0.45; ¹ H-NMR (DMSO-d₆): δ 1.42-1.63 (m, 2H), 1.92-2.04 (m, 2H), 2.51(t, J=7.4 Hz, 2H), 3.61 (s, 2H), 7.09-7.23 (m, 5H), 7.55 (d, J=8.5, 2H),7.77 (d, J=8.8 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.5, 2H).##STR143## Step 4--Preparation of Example 87

The diacid product from step 3 (28.34 g, 62.85 mmol) was dissolved in1,4-dioxane (1.2 L) and was held at reflux under argon overnight.Concentration gave the crude product as a yellow-white solid (27.60 g)which was recrystallized from toluene to deliver the title compoundExample 87 as a tan solid (21.81 g, 53.60 mmol) after overnight dryingin a vacuum oven at 100° C. The decarboxylation was repeated on theremaining diacid (12.38 g) from step 3 to give additional recrystallizedproduct (7.60 g, 18.68 mmol). The total yield for the decarboxylationstep was 80%. The final product contains 5 mol % toluene even afterextensive vacuum oven drying at 100° C.

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)=0.64; ¹ H-NMR (DMSO-d₆) δ 1.62-1.71 (m, 4H), 2.54-2.63 (m, 2H),2.79-2.91 (m, 1H), 3.11 (dd, J=4.1 Hz and 18 Hz, 1H), 3.39 (dd, J=9.6 Hzand 18 Hz, 1H), 7.12-7.28 (m, 5H), 7.54 (d, J=8.8 Hz, 2H), 7.77 (d,J=8.8 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 8.04 (d, J=8.5 Hz, 2H); MS(FAB-LSIMS) 407 M+H!⁺ (C₂₅ H₂₃ O₃ Cl, FW=406.91); Anal. (for C₂₅ H₂₃ O₃Cl.0.05C₇ H₈) C: calcd, 73.99; found, 73.75. H: calcd, 5.73; found,5.74.

Resolution of Example 87

Purification of Dehydroabietylamine

A solution of dehydroabietylamine (60%, 100 g, 0.21 mol) in toluene (170mL) was treated with a second solution of glacial acetic acid (24 mL) intoluene (55 mL) at room temperature. The mixture was stored at roomtemperature overnight. The crystalline salt was collected by filtration,washed with cold toluene and recrystallized from boiling toluene (152mL). The crystals were collected by filtration, washed with n-pentaneand air-dried to give dehydroabietylamine acetate (47 g, 78%) as a whitecrystalline solid.

A solution of dehydroabietylamine acetate (47 g, 0.16 mol) in water (175mL) was gently warmed until the solution became homogeneous. An aqueoussolution of NaOH (10% W/V, 61 mL) was carefully added and after coolingto room temperature. The aqueous solution was extracted with diethylether, dried over MgSO₄, filtered and concentrated to givedehydroabietylamine (35 g, 58%) as a viscous oil which solidified onstanding.

Mp 44°-45° C.; α!D +54° (c 2.3, acetone); ¹ H NMR (CDCl₃) δ 7.19 (d,J=8.1 Hz, 1 H), 6.99 (dd, J₁ =8.1 Hz, J₂ =1.8 Hz, 1 H), 6.89 (m, 1 H),2.78 (m, 3 H), 2.62 (d, J=13.2 Hz, 1 H), 2.45 (d, J=13.2 Hz, 1 H), 2.30(dt, J₁ =12.9 Hz, J₂ =3 Hz, 1 H), 1.73 (m, 3 H), 1.51 (m, 4 H), 1.35 (m,3 H), 1.22 (m, 6 H), 0.90 (s, 3 H); ¹³ C NMR (CDCl₃) δ 147.3, 145.3,134.5, 126.6, 124.1, 123.6, 53.7, 44.6, 38.4, 37.2, 37.0, 35.0, 33.3,30.0, 25.1, 23.9, 23.8, 18.6, 18.5, 18.4; MS (FAB) m/z (relativeintensity) 286 (M⁺ +H, 100), 173 (40). Anal. Calcd for C₂₀ H₃₁ N: C,84.15; H, 10.95; N, 4.91. Found C, 83.93; H, 10.78; N, 4.84.

EXAMPLE 88

A solution of Example 87 (45 g, 0.11 mol) and dehydroabietylamine (32 g,0.11 mol) in an acetone/ethanol/water mixture (50:20:1; 1260 mL) wascarefully warmed until the solution became clear (1 h). After cooling toroom temperature and standing for 42 h, the solid was removed byfiltration.

The solid product from the initial crystallization was diluted with a10% dichloromethane/ethyl acetate mixture (700 mL) and treated with 10%phosphoric acid (300 mL). After stirring at room temperature for 1 h,the mixture was added to a separatory funnel and diluted with sat. aq.NaCl (200 mL). After the aqueous phase was drained off, the precipitatethat remained in the organic layer was removed by filtration and driedto give 9.2 g of near racemic solid with an isomer ratio of 48:52(Example 89:Example 88). The remaining solution was filtered through ashort pad of silica gel and concentrated to give Example 88 (13.3 g, 60%theoretical; isomer ratio 0.8:99.2 (Example 89:Example 88)).

HPLC conditions for Example 87 (Example 88 and Example 89):

column: Chiralcel® OJ analytical column

flow rate: 1 mL/min

solvent system: 35% (ethanol; 1% water; 0.2% TFA) in hexanes

detection: l=288

concentration: 1 mg/mL

injection amount: 6 μL

19.8 min. (Example 89); 26.8 min. (Example 88)

EXAMPLE 88

MP 125°-126° C.; α!D +25.7° (c 1.4, acetone); ¹ H NMR (CDCl₃) δ 8.25 (d,J=8.4 Hz, 2 H), 7.65 (d, J=8.7 Hz, 2 H), 7.56 (d, J=8.4 Hz, 2 H), 7.20(d, J=8.4 Hz, 2 H), 7.28 (t, J=7.8 Hz, 2 H), 7.19 (m, 3 H), 3.49 (dd, J₁=16.8 Hz, J₂ =8.4 Hz, 1 H), 3.14 (dd, J₁ =12.9 Hz, J₂ =4.8 Hz, 1 H),3.08 (dd, J₁ =16.8 Hz, J₂ =4.2 Hz, 1H), 2.68 (t, J=7.2 Hz, 2 H), 1.77,(m, 4 H); ¹³ C NMR (CDCl₃) δ 197.4, 180.9, 144.6, 141.8, 138.2, 135.3,134.5, 129.1, 128.7, 128.5, 128.4, 128.3, 127.1, 125.9, 40.1, 40.0,35.6, 31.4, 28.9; MS (FAB) m/z (relative intensity) 407 (M⁺ +H, 100),389 (55), 215 (60). Anal. Calcd for C₂₅ H₂₃ O₃ Cl: C, 73.79; H, 5.70;Cl, 8.71.Found C, 74.02; H, 5.79; Cl, 8.82.

EXAMPLE 89

The filtrate from the initial crystallization was concentrated underreduced pressure. The resulting solid material was processed using thesame procedure as described for Example 88. The analogous sequenceprovided racemate (8.0 g, isomer ratio 57:43) and Example 89 (13.5 g,60% theoretical; isomer ratio 99.1:0.9).

MP 125°-126° C., α!D -25.6° (c 1.4, acetone); ¹ H NMR (CDCl₃) δ 8.25 (d,J=8.4 Hz, 2 H), 7.65 (d, J=8.7 Hz, 2 H), 7.56 (d, J=8.4 Hz, 2 H), 7.20(d, J=8.4 Hz, 2 H), 7.28 (t, J=7.8 Hz, 2 H), 7.19 (m, 3 H), 3.49 (dd, J₁=16.8 Hz, J₂ =8.4 Hz, 1 H), 3.14 (dd, J₁ =12.9 Hz, J₂ =4.8 Hz, 1 H),3.08 (dd, J₁ =16.8 Hz, J₂ =4.2 Hz, 1H), 2.68 (t, J=7.2 Hz, 2 H), 1.77,(m, 4 H); ¹³ C NMR (CDCl₃) δ 197.4, 180.9, 144.6, 141.8, 138.2, 135.3,134.5, 129.1, 128.7, 128.5, 128.4, 128.3, 127.1, 125.9, 40.1, 40.0,35.6, 31.4, 28.9; MS (FAB) m/z (relative intensity) 407 (M⁺ +H, 100),389 (95), 215 (70).

Anal. Calcd for C₂₅ H₂₃ O₃ Cl: C, 73.79; H, 5.70; Cl, 8.71. Found C,73.45; H, 5.87; Cl, 8.97.

Chiral Synthesis of Example 90 ##STR144## Step 1

4-Bromobiphenyl (11.6 g, 50 mmol) was dissolved in 1,2-dichloroethane(25 mL) and added to a suspension of succinic anhydride (5.0 g, 50 mmol)in 1,2-dichloroethane (70 mL) and the mixture was cooled to 0° C. Solidaluminum chloride (14.0 g, 105 mmol) was added in six portions resultingin a dark green solution. After 10 min, the reaction was allowed to warmto rt and stirred a further 72 h under Ar. The reaction mixture waspoured into a beaker containing 200 mL crushed ice/water. Hexane (200mL) was added and the mixture stirred for 1 h. The pale orange solid wasfiltered off to give 16.8 g (100%) of crude acid. A portion of the acid(7.0 g) was then suspended in methanol (25 mL)/toluene (25 mL) and conc.H₂ SO₄ (2.5 mL) was added dropwise. The mixture stirred 14 h at rt thenwas heated to 75° C. for 3 h. The solvent was removed in vacuo and theresidue dissolved in CH₂ Cl₂ and slowly poured into a mixture ofsaturated aqueous sodium bicarbonate/ice. The ester was extracted withmethylene chloride and dried over MgSO₄. Filtration and removal of thesolvent in vacuo gave 6.44 g (88%) of pale yellow powder.

¹ H NMR (300 MHz, CDCl₃) δ 2.81 (t, J=6.6 Hz, 2 H), 3.36 (t, J=6.6 Hz, 2H), 3.73 (s, 3 H), 7.49 (m, 2 H), 7.59 (m, 4 H), 8.07 (dd, J=1.8, 6.6Hz, 2 H); ¹³ C NMR (75 MHz, CDCl₁₃) δ 28.0, 33.5, 51.9, 122.7, 127.7,128.8, 128.9, 132.2, 138.8, 145.7, 173.4, 197.6. ##STR145## Step 2

A solution of 1,2-bis(trimethylsiloxy)ethane (4.8 mL, 20 mmol) in CH₂Cl₂ (1 mL) was cooled to -70° C. Catalytic trimethylsilyltrifluoromethanesulfonate (10 μL, 0.05 mmol) and then methyl esterproduct from step 1 (1.70 g, 5 mmol) dissolved in CH₂ Cl₂ (4 mL) wereadded resulting in a thick slurry. The ice bath was allowed to warm tort (over 3 h) and the reaction stirred a further 24 h before water wasadded. The product was extracted with CH₂ Cl₂ and the organic layerswere dried over sodium sulfate. After filtration, the solvent wasremoved in vacuo and the residue purified by MPLC (15% ethyl acetate/85%hexanes) to give 1.71 g (85%) ester as a colorless powder.

¹ H NMR (300 MHz, CDCl₃) δ 2.28 (m, 2 H), 2.46 (m, 2 H), 3.65 (s, 3H),3.81 (m, 2 H), 4.04 (m, 2 H), 7.45 (dd, J=2.2, 6.6 Hz, 2 H), 7.51 (m, 4H), 7.57 (dd, J=2.2, 6.6 Hz, 2 H); ¹³ C NMR (75 MHz, CDCl₃) δ 28.7,35.4, 51.6, 64.8, 109.5, 121.7, 126.3, 126.8, 128.7, 131.9, 139.7,139.8, 173.9. ##STR146## Step 3

The ketal from step 2 (4.61 g, 12 mmol) was dissolved in THF (45 mL) andH₂ O (15 mL) at rt. NaOH (480 mg, 12 mmol) was added and the reactionstirred at rt for 19 h. Ester was still present by TLC so anotherportion of NaOH (210 mg) was added. After a further 2 h the reaction wasacidified to pH 3 with 4 M HCl at 0° C. and the product was extractedwith ethyl acetate. Removal of solvent in vacuo gave 4.63 g of acolorless solid that was taken on to the next step crude. A portion ofthe acid (2.50 g, 6.6 mmol) was dissolved in CH₂ Cl₂ (37 mL).(S)-(-)-4-Benzyl-2-oxazolidinone (1.44 g, 11.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.56 g, 8.1mmol), and dimethylaminopyridine (181 mg, 1.5 mmol) respectively wereadded at rt. A few minutes after the addition of the DMAP, all solidgoes into solution. The reaction stirred for 3 d at rt and was thenpoured into saturated aqueous NH₄ Cl. The product was extracted with CH₂Cl₂ and dried over sodium sulfate. After removal of the solvent invacuo, the residue was purified by MPLC (2% CH₃ OH/98% CH₂ Cl₂) to give2.64 g (74%) of the above shown benzyloxazolidinone as a colorlesssolid.

¹ H NMR (300 MHz, CDCl₃) δ 2.38 (m, 2 H), 2.72 (dd, J=9.6, 13.2 Hz, 1H), 3.13 (m, 2 H), 3.29 (dd, J=3.3, 13.6 Hz, 1 H), 3.82 (m, 2 H), 4.08(m, 2 H), 4.17 (m, 2 H), 4.52 (m, 1 H), 7.19-7.33 (comp m, 5 H), 7.45(m, 2 H), 7.56 (m, 6 H); ¹³ C NMR (75 MHz, CDCl₃) δ 30.2, 34.7, 37.9,55.3, 64.8, 66.2, 109.6, 121.7, 126.4, 126.8, 127.4, 128.8, 129.0,129.5, 131.9, 135.4, 139.7, 139.8, 141.8, 153.5, 172.9. ##STR147## Step4

A solution of pyridine (0.90 mL, 11 mmol) in CH₂ Cl₂ (33 mL) was cooledto -70° C. Triflic anhydride (1.68 mL, 10 mmol) was added over 6 minresulting in a yellowish, slushy solution. After 5 min,3-phenyl-1-propanol (1.40 mL, 10 mmol) was added over 4 min. Thereaction stirred for 30 min at -70° C. and was then warmed to -20° C.for 75 min. The cold solution was poured through a fritted funnelcontaining silica gel. The silica was washed with CH₂ Cl₂ and thesolvent was removed in vacuo to give the above triflate as a pale orangeliquid which was kept under vacuum until it was used in the nextreaction (approximately 1 h). ##STR148## Step 5

Benzyloxazolidinone from step 3 (1.0 g, 1.9 mmol) was dissolved in THF(5 mL) and cooled to -70° C. Sodium bis(trimethylsilyl)amide (1M in THF,2.0 mL, 2 mmol) was added to the oxazolidinone over 5 min and thereaction stirred a further 30 min. A solution of phenylpropyl triflatefrom step 4 (2.7 g, 10 mmol) in THF (5 mL) and diisopropylethylamine(1.8 mL, 10 mmol) was added to the sodium anion and the reaction stirredfor 2 h at -70° C. The reaction was quenched at -70° C. with saturatedaqueous NH₄ Cl (100 mL) and then the flask was warmed to rt. The solventwas removed in vacuo and the residue was dissolved in ethyl acetate andwashed with saturated aqueous NH₄ Cl. The aqueous layer was extractedwith ethyl acetate and dried over sodium sulfate. After filtration, thesolvent was removed in vacuo and the residue purified by MPLC (20% ethylacetate/80% hexane to 30% ethyl acetate/70% hexane) to afford 66 mg ofrecovered starting oxazolidinone, 34 mg of the (R)-diastereomer productand 630 mg of the (S)-diastereomer product as shown above.

¹³ C NMR (75 MHz, CDCl₃) δ 28.6, 33.6, 35.8, 38.3, 42.3, 55.6, 64.3,64.8, 65.9, 109.6, 119.7, 121.8, 125.8, 126.5, 126.7, 127.3, 128.3,128.5, 128.7, 129.0, 129.5, 132.0, 135.4, 139.7, 141.6, 142.1, 153.3,177.1 ##STR149## Step 6

The product of step 5 (350 mg, 0.53 mmol) was dissolved in THF (3.75 mL)and H₂ O (1.25 mL) and cooled to 0° C. Hydrogen peroxide (30%, 485 mL,4.2 mmol) then lithium hydroxide monohydrate (90 mg, 2.1 mmol) wereadded. After 30 min the ice bath was removed and the reaction stirred 6h at rt. Aqueous sodium bisulfite (10%) was added and the mixturestirred overnight. The aqueous layer was extracted with CH₂ Cl₂ and theorganic solution was dried over sodium sulfate. After filtration theresidue was purified by MPLC (20% ethyl acetate/80% hexanes) to give 31mg of pure acid as shown above and 103 mg of a mixture of startingbenzyl oxazolidinone and the product. The mixed fractions were dissolvedin 30% ethyl acetate/70% hexanes; crystals formed that were 70%oxazolidinone by HPLC while the mother liquor was pure acid product.

¹³ C NMR (75 MHz, CDCl₃) δ 28.9, 32.7, 35.6, 40.3, 42.8, 64.7, 64.8,109.4, 125.8, 126.2, 126.8, 128.3, 128.3, 128.4, 128.4, 128.8, 132.0,139.8, 142.0, 142.1, 181.4. ##STR150## Step 7--Preparation of Example 90

The above ketal from step 6 (38 mg, 0.08 mmol) was dissolved in CH₂ Cl₂(475 mL) and cooled to 0° C. A drop of conc. HClO₄ (9.4 mL) was addedand the reaction stirred for 3.5 h at 0° C. Saturated sodium bicarbonatewas added and the product was extracted with methylene chloride. Thecombined organic portions were dried over sodium sulfate. Removal ofsolvent in vacuo gave material (29 mg, 84%) that was pure by analyticalHPLC analysis.

α!D -22.1° (c 1.2, CHCl₃); ¹ H NMR (300 MHz, CD₃ OD) δ 1.69 (m, 4 H),2.63 (m, 2 H), 2.99 (m 1 H), 3.10 (dd, J=4.4, 18.0, 1 H), 3.45 (dd,J=9.5, 18.0, 1 H), 7.17 (m, 5 H), 7.59 (m, 4 H), 7.72 (m, 2 H), 8.04 (m,2 H ); ¹³ C NMR (75 MHz, CD₃ OD) δ 30.2, 32.8, 36.7, 41.6, 48.3, 123.6,126.8, 129.4, 129.9, 130.0, 133.2, 137.1, 140.2, 143.4, 145.8, 179.3,200.0. ##STR151##

EXAMPLE 91

The title compound was synthesized by a sequence similar to that forproducing Example 87 except commercially available1-(2-bromoethanone)-4-phenyl-benzene was used in the alkylation step 3instead of the 4'-chlorobiphenyl intermediate. The final product waspurified by crystallization from toluene to give a white solid (mp135.0°-137.0° C.) which retained toluene despite extensive drying in avacuum oven.

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.65; ¹ H-NMR (DMSO-d₆): δ 1.54-1.67 (m, 4H), 2.55-2.60 (m, 2H),2.82-2.87 (m, 1H), 3.13 (dd, J=4.0 Hz, 18 Hz, 1H), 3.40 (dd, J=9.6 Hz,18 Hz, 1 H), 7.12-7.28 (m, 5H), 7.38-7.51 (m, 3H), 7.73 (d, J=8.5 Hz,2H), 7.80 (d, J=8.5 Hz, 2H), 8.04 (d, J=8.5 Hz, 2H), 12.13 (s, 1H); MS(FAB-LSIMS) 373 M+H!⁺ (C₂₅ H₂₄ O₃, FW=372.47); HRMS calcd, 372.1725;found, 372.1735.

EXAMPLE 92, EXAMPLE 93, EXAMPLE 94, EXAMPLE 95 and EXAMPLE 96

These compounds were prepared using the general procedure of Example 87except that the indicated commercial malonates were used instead ofethyl 2-carboethoxy-5-phenylpentanoate. ##STR152##

EXAMPLE 92

From diethyl 2-ethylmalonate: MP 151°-152° C.; ¹ H NMR (DMSO) δ 8.03 (d,J=7.6 Hz , 2H); 7.77 (m, 4H); 7.54 (m, 2H); 3.40 (m, 2H); 3.07 (dd,J=17.9 Hz and 4.1 Hz, 1H); 2.78 (m, 1H); 1.59 (m, 2H); 0.91 (t, J=7.4Hz, 3H); ¹³ C NMR (DMSO) δ 199.19, 177.23, 144.24, 138.78, 136.65,134.42, 130.15, 129.88, 129.77, 127.96,42.35, 25.68, 12.49; MS(FAB-LSIMS) 317 M+H!⁺, (C₁₈ H₁₇ CI O₃, FW=316.8); Anal C: calcd, 68.25;found, 68.03. H: calcd, 5.41; found, 5.34. Cl: calcd; 11.19, found;11.19. ##STR153##

EXAMPLE 93

From diethyl 2-propylmalonate: MP 127°-128° C.; ¹ H NMR (DMSO) δ 8.03(d, J=8.4 Hz , 2H); 7.76 (m, 4.1 Hz); 7.53 (d,J=8.4 Hz, 2H); 3.37 (m,2H); 3.08 (dd, J=17.9 Hz and 4.1 Hz, 1H); 2.83 (m, 1H);2.48 (s, 1H);1.53 (m, 2H);1.34 (m, 2H); 0.87 (t, J=7.2 Hz, 3H); ¹³ C NMR (DMSO) δ199.18, 177.40, 144.24, 138.78, 136.63, 134.41, 130.15, 129.88, 129.77,127.96, 120.25, 34.82, 20.88, 14.99; MS (FAB-LSIMS) 331 M+H!⁺, (C₁₉ H₁₉Cl O₃, FW=330.8); Anal C: calcd, 68.99; found, 68.95. H: calcd, 5.79;found, 5.75. Cl: calcd; 10.72, found; 10.77. ##STR154##

EXAMPLE 94

From diethyl 2-allylmalonate: MP 133°-134° C.; ¹ H NMR (DMSO) δ 8.02 (d,J=8.3 Hz , 2H); 7.76 (m, 4H); 7.53 (d, J=8.3 Hz, 2H); 5.78 (m, 1H); 5.04(m, 1H); 3.39 (dd, J=18.2 Hz and 9.4 Hz, 2H); 3.07 (dd, J=18.2 Hz and4.1 Hz, 1H); 2.95 (m, 1H);2.35 (m, 1H); ¹³ C NMR (DMSO) δ 198.93,176.61, 144.28, 138.76, 136.59, 134.43, 130.15, 129.88, 129.72, 128.05,118.33, 36.69; MS (FAB-LSIMS) 329 M+H!⁺, (C₁₉ H₁₇ Cl O₃, FW=328.8); AnalC: calcd, 69.41; found, 25 69.36. H: calcd, 5.21; found, 5.13. Cl:calcd; 10.78, found; 10.67. ##STR155##

EXAMPLE 95

From diethyl 2-butylmalonate: MP 152°-153° C.; ¹ H NMR (DMSO) δ 8.03 (d,J=8.3 Hz , 2H); 7.75 (m, 4H); 7.53 (d, J=8.3 Hz, 2H); 3.38 (dd, J=18.2Hz and 9.5 Hz, 2H); 3.08 (dd, J=17.9 Hz and 4.1 Hz, 1H); 2.81 (m, 1H);1.58 (m, 2H); 1.29 (m, 4H); 0.85 (t, J=6.6 Hz, 3H); ¹³ C NMR (DMSO) δ199.16, 177.40, 144.22, 138.78, 136.61, 134.42, 130.15, 129.88, 129.77,127.96, 32.33, 29.81, 23.20, 14.92; MS (FAB-LSIMS) 345 M+H!⁺, (C₂₀ H₂₁Cl O₃, FW=344.8); Anal C: calcd, 69.66; found, 69.60. H: calcd, 6.14;found, 56.06. Cl: calcd; 10.28, found; 10.24. ##STR156##

EXAMPLE 96

From diethyl 2-propargylmalonate: MP 130°-132° C.; ¹ H NMR (DMSO) δ 8.00(d, J=8.3 Hz , 2H); 7.77 (m, 4H); 7.53 (d, J=8.3 Hz, 2H); 3.52 (dd,J=18.2 Hz and 8.3 Hz, 1H); 3.20 (dd, J=18.2 Hz and 4.7 Hz, 1H); 3.03 (m,1H); 2.90 (t, J=2.5 Hz, 1H) 2.54 (m, 2H); ; ¹³ C NMR (DMSO) δ 198.58,175.43, 144.36, 138.75, 136.52, 134.47, 130.17, 129.88, 129.74, 128.04,120.25, 82.58, 74.29, 21.48,; MS (FAB-LSIMS) 327 M+H!⁺, (C₁₉ H₁₅ Cl O₃,FW=326.8).

EXAMPLE 97 AND EXAMPLE 98

These compounds were prepared using the general method of Example 87except that the indicated alkyl bromides were used in step 1 rather than1-bromo-3-phenylpropane. ##STR157##

EXAMPLE 97

From 1-bromoheptane: MP 118°-120° C.; ¹ H NMR (CDCl₃) δ 8.04 (dd, J=6.6Hz and 1.6 Hz, 2H); 7.64 (d, J=6.9 Hz, 2H); 7.55 (m, 2H); 7.44 (m, 2H);3.48 (m, 1H); 3.08 (m, 2H); 1.75 (m, 1H); 1.67 (m, 1H); 1.37 (m, 10H);0.88 (t, J=6.3 Hz, 3H) ¹³ C NMR (CDCl₃) δ 198.27, 182.09, 145.29,138.92, 136.16, 135.16, 129.81, 129.43, 129.18, 127.76,40.83, 40.78,32.58, 32.46, 30.11, 29.77, 27.81, 23.31, 14.76; MS (FAB-LSIMS) 386.9M+H!⁺, (C₂₃ H₂₇ Cl O₃, FW=386.9). ##STR158##

EXAMPLE 98

From 1-bromodecane: MP 108°-110° C.; ¹ H NMR (CDCl₃) δ 7.99 (d, J=8.5Hz, 2H); 7.59 (d, J=8.5 Hz, 2H); 7.50 (m, 2H); 7.39 (m, 2H); 3.43 (dd,J=18.7 Hz and 9.9 Hz, 1H); 3.00 (m, 2H); 1.67 (m, 1H); 1.56 (m, 1H);1.25 (m, 16H); 0.82 (t, J=6.3 Hz, 3H) ¹³ C NMR (CDCl₃) δ 198.69, 178.51,144.98, 138.91, 136.39, 134.98, 129.73, 129.36, 129.12, 127.63,41.04,40.97, 40.20, 32.71, 32.50, 30.20, 30.07, 29.91, 27.81, 23.27, 14.73; MS(FAB-LSIMS) 429 M+H!⁺, (C₂₆ H₃₃ Cl O₃, FW=429.00).

EXAMPLE 99 ##STR159## Step 1--Preparation of1-(2-Bromoethanone)-4-(4-nitrophenyl)-benzene.

The title compound was prepared via the procedure outlined for Example87 (step 2) using commercially available 4-nitrobiphenyl instead of4-chlorobiphenyl. The final product was recrystallized from ethylacetate to afford orange crystals (52%).

TLC (hexanes-dichloromethane, 1:1): R_(f) =0.55; ¹ H-NMR (DMSO-d₆): δ4.97 (s, 2H), 7.90-8.40 (m, 8H); MS (FAB-LSIMS) 319, 321 M+H!⁺ (C₁₄ H₁₀O₃ NBr, FW=320.15). ##STR160## Step 2--Preparation of Example 99.

The title compound was synthesized by a sequence similar to that forproducing Example 87 except that1-(2-bromoethanone)-4-(4-nitrophenyl)-benzene and commercially availablediethyl phenethyl malonate were used in lieu of the 4-chlorobiphenyl andphenylpropyl malonates respectively. The final product wasrecrystallized from acetone to give orange crystals (MP 193.5°-194.0°C.) which retained acetone despite extensive drying in a vacuum oven.

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)=0.60; ¹ H-NMR (DMSO-d₆): δ 1.70-2.00 (m, 2H), 2.55-2.75 (m, 2H),2.80-2.93 (m, 1H), 3.17-3.25 (m, 1H), 3.48 (dd, J=18.4, 9.6 Hz, 1H),7.10-7.35 (m, 5H), 7.90-8.35 (m, 8H), 12.24 (s, 1H); ¹³ C-NMR (DMSO-d₆):δ 198.32, 176.28, 147.39, 145.45, 142.25, 141.70, 136.60, 128.96,128.49, 127.80, 126.05, 124.34, 33.50, 32.76; MS (El) 403 M!⁺ (C₂₄ H₂₁O₅ N, FW=403.44); Anal. C: calcd, 71.45; found, 71.41. H: calcd, 5.25;found, 5.23. N: calcd, 3.47; found, 3.46. ##STR161##

EXAMPLE 100

A 125-mL Parr reaction vessel containing Example 99 (1.15 g, 2.85 mmol),10% Pd/C (0.06 g), and glacial acetic acid (50 mL) was charged withhydrogen gas at 55 psi and shaken on a Parr apparatus until hydrogenuptake ceased. The Parr reaction vessel was then purged with argon andthe reaction mixture was filtered through a pad of Celite, rinsing withacetone. The solution was concentrated to dryness via rotary evaporationusing hexane to azeotrope the acetic acid. The solid was dissolved inhot 10% HCl, filtered and concentrated to dryness via rotaryevaporation. The crude hydrochloride was then recrystallized fromethanol to afford off-white crystals which when dried in a vacuum oven(80° C., 3 days) became purple (0.18 g, 17%, MP 222.0°-224.0° C.).

TLC (dichloromethane-methanol, 24:1): R_(f) =0.55; ¹ H-NMR (DMSO-d₆): δ1.70-2.00 (m, 2H), 2.55-2.75 (m, 2H), 2.80-2.90 (m, 1H), 3.19 (dd,J=18.0, 4.0 Hz, 1H), 3.46 (dd, J=18.0, 9.6 Hz, 1H), 7.10-7.30 (m, 5H),7.37 (d, J=8.5 Hz, 2H), 7.80 (d, J=8.5 Hz, 4H), 8.05 (d, J=8.1 Hz, 2H),8.50-11.0 (br s, 4H); ¹³ C NMR (DMSO-d₆): δ 198.19, 176.31, 143.79,141.73, 136.65, 135.44, 135.11, 128.90, 128.54, 128.49, 128.40, 126.84,126.05, 122.55, 33.53, 32.79; MS (El) 373 M-HCl!⁺ (C₂₄ H₂₄ O₃ NCl,FW=409.92); Anal. C: calcd, 70.32; found, 70.38. H: calcd, 5.90; found,5.98. N: calcd, 3.42; found, 3.37.

EXAMPLE 101 ##STR162## Step 1--Preparation of1-(2-Bromoethanone)-4-(4-cyanophenyl)-benzene.

This material was prepared by a procedure similar to that outlined inthe preparation of Example 87 (step 2), using commercially available4-biphenylcarbonitrile instead of 4-chlorobiphenyl. The final productwas recrystallized from ethyl acetate-hexanes to give an off-white solid(63%).

TLC (hexanes-ethyl acetate, 3:1): R_(f) =0.54; ¹ H NMR (CDCl₃): δ 4.48(s, 2H), 7.71-7.80 (m, 6H), 8.11 (d, J=8.5 Hz, 2H); MS (EI) 299, 301 M!⁺(C₁₅ H₁₀ ONBr, FW=300.16). ##STR163## Step 2--Preparation of Example101.

The title compound was synthesized by a sequence similar to that forproducing Example 87 except that1-(2-bromoethanone)-4-(4-cyanophenyl)-benzene and commercially availablediethyl phenethyl malonate were used in lieu of the 4-chlorobiphenyl andphenylpropyl malonate respectively. The final product was recrystallizedfrom ethanol/hexane to give off-white crystals (mp 181.0°-182.0° C.)which retained ethanol and hexane despite extensive drying in a vacuumoven.

TLC (chloroform-methanol, 19:1 with trace amount of acetic acid): R_(f)=0.53; ¹ H-NMR (DMSO-d₆): δ 1.80-1.95 (m, 2H), 2.62-2.68 (m, 2H),2.82-2.87 (m, 1H), 3.21 (dd, J=18.1, 9.6 Hz, 1H), 7.16-7.30 (m, 5H),7.90 (d, J=8.5 Hz, 2H), 7.95 (s, 4H), 8.08 (d, J=8.7 Hz, 2H); ¹³ C NMR(DMSO-d₆): δ 198.29, 176.33, 143.53, 142.72, 141.73, 136.41, 133.14,128.93, 128.56, 128.51, 128.12, 127.60, 126.07, 118.93, 111.11, 40.09,33.55, 32.82; MS (FAB-LSIMS) 384 M+H!⁺ (C₂₅ H₂₁ O₃ N, FW=383.45); HRMScalcd. 383.1521, found 383.1531.

EXAMPLE 102 ##STR164## Step 1--Preparation of 2-(2-lodophenyl)ethanol.

A solution of o-iodophenylacetic acid (19.87 g, 75.83 mmol) in drytetrahydrofuran (110 mL) was added dropwise over 41 min to a solution ofborane in tetrahydrofuran (151 mL of 1M solution, ca. 151.0 mmol) whichwas cooled with an ice-water bath. The reaction was stirred at 0° to 10°C. for 2 hr 15 min. After the reaction mixture was cooled to 0° C., itwas quenched by cautious addition (frothing|) of 10 (vol.) % acetic acidin methanol over 20 min. Stirring was continued for 25 min before thereaction was concentrated on a rotary evaporator. The residue wasdissolved in ethyl acetate and washed with saturated ammonium chloridefollowed by saturated sodium bicarbonate. The organics were dried (Na₂SO₄) and concentrated to a yellow oil (18.07 g) which was used in thenext step without purification.

TLC (hexane-ethyl acetate, 1:1): R_(f) =0.71; ¹ H-NMR (DMSO-d₆): δ 2.81(t, J=7.2 Hz, 2H), 3.53 (dt, J=5.1 Hz, 7.5 Hz, 2H), 4.73 (t, J=5.4 Hz,1H), 6.90-6.95 (m, 1H), 7.29 (dd, J=4.9 Hz, 0.8 Hz, 2H), 7.79 (d, J=7.7Hz, 1H); MS (EI) 248 M!⁺ (C₈ H₉ IO, FW=248.07). ##STR165## Step2--Preparation of 2-(2-lodophenyl)ethyl bromide.

Neat 2-(2-iodophenyl)ethanol (17.75 g, 71.55 mmol) was treated dropwisewith phosphorous tribromide (3.5 mL, 36.85 mmol) over 6 min while thereaction vessel was placed in a water bath to modulate the exothermicreaction. Stirring was continued for 15 min at room temperature and thenfor 2 hr while the mixture was heated in an oil bath at 100° C. Thereaction was cooled to room temperature, diluted with ether and quenchedcarefully with water (frothing/exotherm|). The layers were separated,the organics were washed with saturated sodium bicarbonate and dried(Na₂ SO₄). Concentration gave a yellow oil which was purified byKugelrohr distillation (140° C./700 millitorr) to give a colorless oil(19.50 g, 62.71 mmol; 83% yield for above two steps).

TLC (hexane-ethyl acetate, 20:1): R_(f) =0.79; ¹ H-NMR (DMSO-d₆): δ 3.20(t, J=7.5 Hz, 2H), 3.64 (t, J=7.5 Hz, 2H), 4.73 (t, J=5.4 Hz, 1H),6.97-7.02 (m, 1H), 7.31-7.39 (m, 2H), 7.81-7.84 (m, 1H); MS (EI) 310,312 M!⁺ (C₈ H₈ Brl FW=310.96). ##STR166## Step 3--Preparation of Example102.

The title compound was synthesized by a sequence similar to that forExample 87 except that 2-(2-iodophenyl)ethyl bromide and commerciallyavailable diethyl phenethyl malonate were used in lieu of the4-chlorobiphenyl and phenylpropyl malonate respectively. The finalproduct was recrystallized from chloroform to give a fluffy, white solid(mp: melts/softens over a broad range starting at 50° C.; the bulk ofthe sample melts at 189°-190° C.).

TLC (chloroform-methanol, 20:1 with a trace of acetic acid): R_(f)=0.49; ¹ H-NMR (DMSO-d₆): δ 1.70-1.93 (m, 2H), 2.71-2.77 (m, 2H),2.87-2.93 (m, 1H), 3.23 (dd, J=4.1 Hz, 18.0 Hz, 1H), 3.49 (dd, J=9.5 Hz,18.3 Hz, 1H), 6.91-6.97 (m, 1H), 7.32 (d, J=3.9 Hz, 2H), 7.53-7.57 (m,2H), 7.75-7.84 (m, 5H), 8.06 (d, J=8.5 Hz, 2H), 12.3 (br, 1H); MS (EI)518 M!⁺ (C₂₄ H₂₀ ClIO₃, FW=518.78); Anal. C: calcd, 55.57; found, 55.34.H: calcd, 3.89; found, 3.79. I: calcd, 24.46; found, 24.76. ##STR167##

EXAMPLE 103

Acid Example 102 was dissolved in dimethylsulfoxide (1.5 mL) andmethanol (1 mL). Triethylamine (0.21 mL, 1.51 mmol) was added followedby palladium(II) acetate (12.8 mg, 0.057 mmol) and1,3-bis(diphenyl-phosphino)propane (23.0 mg, 0.056 mmol). Carbonmonoxide was bubbled through the solution for three minutes. The orangesolution was placed under a carbon monoxide atmosphere and was heated inan oil bath at 70°-75° C. The reaction was worked up after 20 hr 45 minof heating. The mixture was cooled to room temperature, diluted withethyl acetate and washed with 10% HCl followed by water. The organicswere dried (Na₂ SO₄) and concentrated to a yellow solid. This materialwas purified by crystallization from hot hexane/ethyl acetate or fromhot toluene/hexane to give the title compound as a tan solid (109.6 mg,0.243 mmol, 50%).

MP 129°-130° C., TLC (chloroform-methanol, 10:1): R_(f) =0.16; ¹ H-NMR(DMSO-d₆): δ 1.70-1.93 (m, 2H), 2.80-3.05 (m, 3H), 3.19 (dd, J=3.9 Hz,18.0 Hz, 1H), 3.47 (dd, J=9.5 Hz, 18.0 Hz, 1H), 3.80 (s, 3H), 7.28-7.36(m, 2H), 7.47-7.57 (m, 3H), 7.74-7.84 (m, 5H), 8.05 (d, J=8.5 Hz, 2H),12.2 (br, 1H); MS (FAB-LSIMS) 451 M+H!⁺ (C₂₆ H₂₃ ClO₅, FW=450.92); Anal.(for C₂₆ H₂₃ ClO₅. 50.3 H₂ O) C: calcd, 68.44; found, 68.58. H: calcd,5.21; found, 5.25. Cl: calcd, 7.77; found, 7.91.

EXAMPLE 104, EXAMPLE 105, and EXAMPLE 106

The general methods of Example 87, steps 3 and 4 were used to prepareExample 104, Example 105, and Example 106 using commercially available2-arylmalonates rather than ethyl 2-carboethoxy-5-phenylpentanoate asindicated below. ##STR168##

EXAMPLE 104 (Reference with respect to composition)

From diethyl phenylmalonate: TLC (3:1 methylene chloride to methanol +2drops acetic acid) R_(f) =0.77; ¹ H NMR (MeOD) δ 8.03 (d, J=8.8 Hz, 2H),7.69 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.43 (d, J=6.6 Hz, 2H),7.28 (m, 5H), 4.19 (dd, J=10.3, 4.1 Hz, 1H, CH₂ CO), 3.91 (dd, J=14.0,10.3 Hz, 1H, CH₂ CO), 3.27 (dd, J=14.0, 4.1 Hz, 2H, CHCOOH). ##STR169##

EXAMPLE 105

From diethyl benzylmalonate: MP 167°-171° C.; ¹ H NMR (DMSO-d₆) δ 12.28(bs, 1 H, COOH), 7.98 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.5 Hz, 2H), 7.74(d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.24 (m, 5H), 3.32 (dd,J=17.8, 9.0 Hz, 2H, CH₂ CO), 3.14 (m, 1H, CHCOOH), 2.99 (dd, J=17.7, 4.1Hz, 2H, CH₂ Ph), 2.81 (m, 1H, CH₂ CO); ¹³ C NMR (DMSO-d₆) δ 198.87,176.49, 144.30, 140.05, 138.75, 136.53, 134.43, 130.15, 130.11, 129.88,129.67, 129.43, 127.99, 127.44, 42.96, 39.76, 38.20; Anal. C: calcd,72.03; found, 71.87. H: calcd, 5.22; found, 5.01. ##STR170##

EXAMPLE 106

From diethyl 2-phenethylmalonate. MP 179° C.; ¹ H NMR (DMSO-d₆) δ 12.29(bs, 1H, COOH), 8.05 (d, J=8.5 Hz, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.76 (d,J=8.5 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.21 (m, 5H), 3.45 (m, 2H, CH₂CO), 2.85 (m, 1H, CHCOOH), 2.66 (m, 2H, CH₂ Ph), 1.87 (m, 2H, CH₂ CH₂Ph); 13C NMR (DMSO-d₆) δ 199.13, 177.25, 144.28, 142.64, 138.79, 136.63,134.45, 130.15, 129.88, 129.80, 129.45, 129.41, 127.96, 126.97, 40.60,40.55, 34.47, 33.72; Anal. C: calcd, 73.37; found, 73.68. H: calcd,5.39; found, 5.43.

EXAMPLE 107 ##STR171## Step 1

Diethylmalonate (2.46 mL, 16.2 mmol) was added dropwise over 20 min to asuspension of sodium hydride (0.43 g, 17.8 mmol) in THF (24 mL) at 0° C.The solution was allowed to stir for 20 min then4(4'-chlorophenyl)-α-bromoacetophenone (5.0 g, 16.2 mmol) in THF (24 mL)was added over 20 min. The reaction was warmed to rt and stirred afurther 12 h then poured into EtOAc (250 mL) and water (250 mL). Thephases were separated and the aqueous phase was extracted with EtOAc(2×100 mL). The combined organic phases were washed with 1M phosphoricacid (2×200 mL), saturated sodium bicarbonate (2×200 mL), and brine (100mL) then dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting oil was purified by flash chromatography on silica gel using agradient of ethyl acetate/hexane (10% to 50% ethyl acetate) as theeluent to afford a crystalline solid which was recrystallized usinghexane and ethyl acetate to afford ethyl 2-carboethoxy-44'-(4"-chlorophenyl)phenyl!-4-oxobutanoate (1.24 g, 20%).

¹ H NMR (CDCl₃) δ 8.06 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.56(d, J=8.5 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 4.26 (q, J=7.4 Hz, 4H, CH₂CH₃), 4.09 (t, J=7.0 Hz, 1H, CH(CO₂ Et)2, 3.66 (d, J=7.0 Hz, 2H, CH₂CO), 1.31 (t, J=7.0 Hz, 6H, CH₃); ¹³ C NMR (CDCl₃) δ 196.72, 169.72,145.53, 138.87, 135.71, 135.21, 129.83, 129.51, 129.20, 127.81, 62.47,47.90, 38.49, 14.71. ##STR172## Step 2--Preparation of4-phenyl-1-iodobutane

Sodium iodide (8.9 g, 59.2 mol) and 4-phenyl-1-chlorobutane (5.0 g, 29.6mol) were added to acetone (29.6 mL) at rt. The mixture was heated to70° C. for 12 h. The resulting solution was gravity filtered to removesalts. The solvent was removed under reduced pressure and excess saltswere dissolved in water (100 mL). Hexane (100 mL) was added to theaqueous mixture. The phases were separated and the organic phase waswashed with saturated sodium bisulfite solution (3×50 mL), treated withdecolorizing carbon, and gravity filtered. The organic layer was thendried (MgSO₄), filtered, and concentrated in vacuo to afford4-phenyl-1-iodobutane (6.94 g, 90%).

The general method of the preparation of 4-phenyl-1-iodobutane was usedto prepare 5-phenyl-1-iodopentane, 6-phenyl-1-iodohexane, and4-(iodomethyl)biphenyl using commercially available5-phenyl-1-chloropentane, 6-phenyl-1-chlorohexane, and4-(chloromethyl)biphenyl. ##STR173## Step 3--Preparation of 1-4'-(4"-chlorophenyl)phenyl!-3,3-dicarboethoxy-1-oxo-7-phenylheptane

Ethyl 2-carboethoxy-4 4'-(4"-chlorophenyl) phenyl!-4-oxobutanoate (0.40g, 1.02 mmol) was added in one portion at rt to a solution of sodiumethoxide (0.08 g, 1.12 mmol) in DME (1 mL). After 15 min,4-phenyl-1-iodobutane (0.24 g, 0.93 mmol) in DME (3 mL) was added. Theresulting solution was stirred for 18 h. The solvent was concentrated invacuo and the resulting oil dissolved in CH₂ Cl₂ (100 mL) and washedwith water (100 mL). The phases were separated and the aqueous phase wasextracted with CH₂ Cl₂ (2×50 mL). The combined organic phases were dried(MgSO₄), filtered, and concentrated in vacuo. The resulting oil waspurified by flash chromatography on silica gel using a gradient of ethylacetate/hexane (10% to 25% ethyl acetate) as the eluent to afford acrystalline solid which was recrystallized with hexane and ethyl acetateto afford 1-4'-(4"-chlorophenyl)phenyl!-3,3-dicarboethoxy-1-oxo-7-phenylheptane(0.272 g, 28%).

MP 67°-69° C.; ¹ H NMR (CDCl₃) δ 8.05 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.5Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.16(m, 5H),4.21 (q, J=7.0 Hz, 4H, CH₂ CH₃), 3.70 (s, 2H, CH₂ CO), 2.58 (t, J=7.7 Hz, 2H, CH₂ Ph), 2.16 (t, J=8.5 Hz, 2H, CH₂ C), 1.61 (m, 2H), 1.26 (m,8H); ¹³ C NMR (CDCl₃) δ 196.88, 171.64, 145.37, 142.82, 138.91, 136.26,135.21, 129.85, 129.41, 129.18, 129.01, 128.89, 127.78, 126.33, 62.20,56.11, 41.93, 36.02, 33.43, 32.01, 24.83, 14.67; Anal. C: calcd, 71.46;found, 71.00. H: calcd, 6.38; found, 6.33. ##STR174## Steps 4 and5--Preparation of Example 107.

The diester from step 3 was converted to the monoacid following thegeneral method for Example 40 (steps 4 and 5).

EXAMPLE 107

MP 127°-130° C.; ¹ H NMR (DMSO-d₆) δ 12.12 (bs, 1H, COOH), 8.03 (d,J=7.3 Hz, 2H), 7.81 (d, J=7.3 Hz, 2H), 7.77 (d, J=7.3 Hz, 2H), 7.54 (d,J=7.3 Hz, 2H), 7.20 (m, 5H), 3.35 (dd, J=19.1, 10.3 Hz, 1H, CH₂ CO),3.08 (dd, J=19.1, 4.4 Hz, 1H, CH₂ CO), 2.81 (m, 1H, CHCOOH), 2.55 (t,J=7.3 Hz, 2H, CH₂ Ph), 1.56 (m, 4H), 1.35 (m, 2H, CH₂ CH₂ CH); ¹³ C NMR(DMSO-d₆) δ 199.16, 177.34, 144.23, 143.25, 138.77, 136.60, 134.41,130.17, 129.88, 129.75, 129.36, 129.31, 127.97, 126.73, 40.03, 39.74,36.07, 32.38, 32.04, 27.26; MS (FAB-LSIMS) 421 (M+H)⁺ (C₂₆ H₂₅ O₃ Cl,FW=420).

EXAMPLE 108, EXAMPLE 109, and EXAMPLE 110.

The general method of Example 107 was improved in Step 1 as shown belowto prepare Example 108, Example 109, and Example 110. The other stepswere not modified. The indicated aryl halides were used instead of4-phenyl-1-iodobutane as described below. ##STR175## Step 1--Preparationof Methyl 2-carbomethoxy-4 4'-(4"-chloro phenyl)phenyl!-4-oxobutanoate

Dimethyl malonate (5.7 mL, 50.0 mmol) was added in one portion to asolution of sodium methoxide (6.6 g, 50.0 mmol) in DME (45 mL) at rt andstirred for 15 min. In a separate reaction vessel,4(4'-chlorophenyl)-α-bromoacetophenone (14.0 g, 45.0 mmol) was dissolvedin DME (136 mL) along with sodium iodide (6.7 g, 45.0 mmol). The Nalsolution was allowed to stir for 15 min at rt. The sodiumdimethylmalonate solution was cannulated dropwise into the4(4'-chlorophenyl)-(α-bromoacetophenone solution; stirring continued 1hr at rt. The solvent was removed in vacuo and the resulting oildissolved in 1:1 methylene chloride:diethyl ether (700 mL). The organicphase was washed with water (250 mL), and saturated sodium chloridesolution (250 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo. The resulting oil was recrystallized using 4:1chloroform:methanol with hexane to precipitate the methyl2-carbomethoxy-4 4'-(4"-chloro phenyl)phenyl!-4-oxobutanoate (10.43 g,64%).

¹ H NMR (DMSO) δ 8.06 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.56(d, J=8.5 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.95 (t, J=7.0 Hz, 1H, CH(CO₂Me)₂), 3.70 (s, J=7.0 Hz, 6H, Me), 3.66 (s, 2H, CH₂ CO); ¹³ C NMR(CDCl₃) δ 196.22, 169.03, 143.56, 137.58, 134.75, 133.44, 129.09,128.84, 128.74, 126.98, 52.60, 46.59, 37.59. ##STR176##

EXAMPLE 108

From 5-phenyl-1-iodopentane and the above Methyl 2-carbomethoxy-44'-(4"-chloro phenyl)phenyl!-4-oxobutanoate.

MP 131°-132° C.; ¹ H NMR (DMSO-d₆) δ 12.14 (s, 1H, COOH), 8.06 (d, J=8.1Hz, 2H), 7.83 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.5Hz, 2H), 7.19 (m, 5H), 3.38 (dd, J=18.4, 9.6 Hz, 1H, CH₂ CO), 3.14 (dd,J=19.1, 4.4 Hz, 1H, CH₂ CO), 2.84 (m, 1H, CHCOOH), 2.56 (t, J=7.4 Hz,2H, CH₂ Ph), 1.57 (m, 4H, CH₂), 1.33 (m, 4H, CH₂); ¹³ C NMR (DMSO-d₆) δ198.10, 176.29, 143.14, 137.68, 136.60, 135.53, 133.33, 129.06, 128.79,128.79, 128.68, 128.26, 128.21, 126.87, 40.32, 40.05, 35.06, 31.42,30.84, 28.56, 26.29; Anal. C: calcd, 74.56; found, 74.25. H: calcd,6.26; found, 6.15. ##STR177##

EXAMPLE 109

From 6-phenyl-1-iodohexane and the above Methyl 2-carbomethoxy-44'-(4"-chloro phenyl)phenyl!-4-oxobutanoate.

MP 104°-105° C.; ¹ H NMR (DMSO-d₆) δ 12.10 (bs, 1H, COOH), 8.06 (d,J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.56 (d,J=8.5 Hz, 2H), 7.18 (m, 5H), 3.37 (m, 1H, CH₂ CO), 3.13 (dd, J=4.4, 2.2Hz, 1H, CH₂ CO), 2.82 (m, 1H, CHCOOH), 2.55 (t, J=7.4 Hz, 2H, CH₂ Ph),1.57 (m, 4H, CH₂), 1.24 (m, 6H, CH₂); ¹³ C NMR (DMSO-d₆) δ 198.11,176.30, 143.14, 142.30, 137.68, 136.60, 135.53, 129.06, 128.79, 128.69,128.26, 128.21, 126.87, 125.58, 40.32, 40.05, 35.12, 35.06, 30.94,28.77, 28.50, 26.43; Anal. C: calcd, 74.90; found, 74.77. H: calcd,6.51; found, 6.41. ##STR178##

EXAMPLE 110

From 4-(iodomethyl)biphenyl and the above Methyl 2-carbomethoxy-44'-(4"-chloro phenyl)phenyl!-4-oxobutanoate.

MP 228°-230° C.; ¹ H NMR (DMSO-d₆) δ 12.32 (s, 1H, COOH), 8.02 (d, J=8.5Hz, 2H), 7.78 (m, 4H), 7.66 (m, 6H), 7.44 (m, 2H), 7.32 (m, 3H), 3.44(dd, J=18.0, 9.2 Hz, 1H, CH₂ CO), 3.20 (m, 1H, CHCOOH), 3.07 (m, 2H, CH₂CO, CH₂ -Biphenyl), 2.90 (m, 1H, CH₂ -Biphenyl); ¹³ C NMR (DMSO-d₆) δ197.80, 175.43, 143.18, 140.94, 139.89, 138.26, 138.18, 137.64, 135.45,129.63, 129.05, 128.89, 128.77, 128.60, 127.26, 126.88, 126.59, 126.50,41.86, 38.94, 38.66; Anal. C: calcd, 76.56; found, 76.11. H: calcd,5.10; found, 4.88. ##STR179##

EXAMPLE 111

The general method of Bay 13-6465 was used to prepare Example 111 usingcommercially available cinnamyl bromide with 0.9 eq of Nal, instead of5-phenyl-1-iodopentane in Step 3.

MP 171°-172° C.; ¹ H NMR (DMSO-d₆) δ 12.25 (s, 1H, COOH), 8.06 (d, J=8.5Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5Hz, 2H), 7.40 (d, J=5.9 Hz, 2H), 7.30 (d, J=5.9 Hz, 1H), 7.21 (d, J=5.9Hz, 2H), 6.47 (d, J=16.2 Hz, 1H, CHCH₂), 6.33 (m, 1H, CHPh), 3.48 (dd,J=18.4, 8.5 Hz, 1H, CH₂ CO), 3.18 (dd, J=18.4, 4.4 Hz, 1H, CH₂ CO), 3.05(m, 1H, CHCOOH), 2.55 (m, 2H, CH₂); ¹³ C NMR (DMSO-d₆) δ 197.93, 175.51,143.15, 137.68, 135.51, 133.31, 131.68, 129.05, 128.77, 128.64, 128.50,127.27, 127.17, 126.87, 126.01, 40.13, 39.11, 34.83; Anal. C: calcd,73.37; found, 72.94. H: calcd, 5.39; found, 5.08.

EXAMPLE 112 and EXAMPLE 113 ##STR180## Preparation of3-(p-methylphenyl)-1-iodopropane:

Potassium iodide (0.90 g, 5.4 mmol) and 3-(p-methylphenyl)propan-1-ol(0.4 g, 2.7 mmol) was added to 85% phosphoric acid (5.4 mL) at rt. Thesolution was heated to 120° C. for 3 h, during which time an oilseparated from the acid layer. The mixture was cooled to rt and pouredinto 150 mL of water and 150 mL of diethyl ether. The organic layer wasseparated, decolorized with saturated sodium bisulfite solution (100mL), and washed with saturated sodium chloride solution (100 mL). Theorganic layer was then dried (MgSO₄), filtered, and concentrated invacuo to afford 3-(4-methylphenyl)-1-iodopropane (0.48 g, 68%).

The general method of the preparation of3-(4-methylphenyl)-1-iodopropane was used to prepare3-(4-chlorophenyl)-1-iodopropane using 3-(4-chlorophenyl) propan-1-ol,3-(4-hydroxyphenyl)-1-iodopropane, 4-hydroxyphenethyl iodide, and3-hydroxyphenethyl iodide using commercially available3-(4-hydroxyphenyl)-1-propanol, 4-hydroxyphenethyl alcohol, and3-hydroxyphenethyl alcohol respectively.

The general method of Example 108 was used to prepare Example 112 andExample 113 using the aryl halides instead of 5-phenyl-1-iodopentane, asindicated below. ##STR181##

EXAMPLE 112

From 3-(4-methylphenyl)-1-iodopropane: MP 158°-159° C.; ¹ H NMR(DMSO-d₆) δ 12.40 (s, 1H, COOH), 8.30 (d, J=8.1 Hz, 2H), 8.07 (d, J=8.1Hz, 2H), 8.03 (d, J=8.5 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.32 (m, 4H),3.60 (dd, J=13.2, 9.9 Hz, 1H, CH₂ CO), 3.39 (dd, J=19.1, 4.1 Hz, 1H, CH₂CO), 3.04 (m, 1H, CHCOOH), 2.77 (m, 2H, CH₂ Ph), 2.50 (s, 3H, CH₃), 1.86(m, 4H, CH₂); ¹³ C NMR (DMSO-d₆) δ 198.04, 176.24, 143.13, 138.76,137.67, 135.49, 134.53, 133.31, 129.05, 128.81, 128.78, 128.68, 126.16,126.84, 40.32, 40.05, 34.59, 31.11, 28.58, 20.61; Anal. C: calcd, 74.19;found, 73.89. H: calcd, 5.99; found, 5.95. ##STR182##

EXAMPLE 113

From 3-4-chlorophenyl-1-iodopropane: MP 148--149° C.; ¹ H NMR (DMSO-d₆)δ 12.16 (s, 1H, COOH), 8.06 (d, J=8.5 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H),7.78 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.1, 2H),7.23 (d, J=8.5, 2H), 3.39 (dd, J=18.0, 9.6 Hz, 1H, CH₂ CO), 3.13 (dd,J=18.4, 4.4 Hz, 1H, CH₂ CO), 2.86 (m, 1H, CHCOOH), 2.59 (m, 2H, CH₂ Ph),1.61 (m, 4H, CH₂); ¹³ C NMR (DMSO-d₆) δ 198.04, 176.22, 143.13, 140.94,137.68, 135.48, 133.31, 130.29, 130.18, 129.07, 128.79, 128.68, 128.17,126.85, 40.32, 34.59, 34.23, 31.00, 28.33; Anal. C: cald, 68.04; found,67.75. H: cald, 5.02; found, 4.95.

EXAMPLE 114, EXAMPLE 115, AND EXAMPLE 116 ##STR183##

Anhydrous potassium carbonate (4.14 g, 30.0 mmol), iodomethane (3.74 mL,60.0 mmol), and 3-(4-hydroxyphenyl)-1-iodopropane (1.58 g, 6.0 mmol)were added to acetone (25 mL) at rt. The mixture was heated to 70° C.for 8 h. The resulting solution was gravity filtered to remove salts andthe filtrate was concentrated in vacuo to afford3-(4-methoxyphenyl)-1-iodopropane (1.22 g, 73%).

The general method of the preparation of3-(4-methoxyphenyl)-1-iodopropane was used to prepare 4-methoxyphenethyliodide, and 3-methoxyphenethyl iodide from 4-hydroxyphenethyl iodide and3-hydroxyphenethyl iodide.

The general method of Example 108 was used to prepare Example 114,Example 115, and Example 116 using, as previously stated,3-(4-methoxyphenyl)-1-iodopropane, 4-methoxyphenethyl iodide, and3-methoxyphenethyl iodide instead of 5-phenyl-1-iodopentane, asindicated below. ##STR184##

EXAMPLE 114

From 3-(4-methoxyphenyl)-1-iodopropane: MP 125°-126° C.; ¹ H NMR(DMSO-d₆) δ 12.05 (bs, 1H, COOH), 8.06 (d, J=8.5 Hz, 2H), 7.80 (m, 4H),7.56 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.1, 2H),3.68 (s, 3H, CH₃), 3.39 (m, 1H, CH₂ CO), 3.14 (m, 1H, CH₂ CO), 2.80 (m,1H, CHCOOH), 2.60 (m, 2H, CH₂ Ph), 1.59 (m, 4H, CH₂); ¹³ C NMR (DMSO-d₆)δ 198.06, 176.25, 157.35, 143.14, 135.51, 133.75, 129.19, 129.06,128.79, 128.69, 128.62, 126.90, 126.85, 113.65, 54.93, 40.34, 38.95,38.66, 34.14, 28.77; Anal. C: calcd, 71.47; found, 71.27. H: calcd,5.77; found, 5.55. ##STR185##

EXAMPLE 115

From 4-methoxyphenethyl iodide: MP 127°-129° C.; ¹ H NMR (DMSO-d₆) δ8.81 (bs, 1H, COOH), 7.87 (d, J=8.5 Hz, 2H), 7.50 (d, 8.5 Hz, 2H), 7.42(d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5, 2H), 6.66 (d,J=8.5, 2H), 3.62 (s, 3H, CH₃), 3.37 (m, 1H, CHCOOH), 2.93 (m, 2H, CH₂CO), 2.53 (m, 2H, CH₂ Ph), 2.05 (m, 1H, CHCH), 1.90 (m, 1H, CHCH); ¹³ CNMR (DMSO-d₆) δ 197.43, 176.88, 157.44, 143.99, 137.90, 135.33, 133.21,128.97, 128.76, 128.36, 128.16, 126.85, 126.66, 113.43, 54.86, 32.14,29.29, 29.25, 24.40; MS (FAB-LSIMS) 423 (M+H)⁺ (C₂₅ H₂₃ O₄ Cl, FW=422).##STR186##

EXAMPLE 116

From 3-methoxyphenethyl iodide. MP 155°-156° C.; ¹ H NMR (DMSO-d₆) δCOOH (not seen), 8.08 (d, J=8.1 Hz, 2H), 7.81 (m, 4H), 7.57 (d, 8.5 Hz,2H), 7.20 (m, 1H), 6.80 (m, 3H), 3.73 (s, 3H, CH₃), 3.45 (m, 1H,CHCOOH), 3.10 (m, 1H, CH₂ CO), 2.90 (m, 1H, CH₂ CO), 2.65 (m, 2H, CH₂Ph), 1.90 (m, 2H, CH₂); ¹³ C NMR (DMSO-d₆) δ 198.06, 176.12, 159.29,143.16, 143.11, 137.68, 129.35, 129.07, 128.81, 128.71, 126.87, 120.54,113.95, 111.29, 54.88, 38.47, 38.31, 33.17, 32.64; MS (FAB-LSIMS) 423(M+H)⁺ (C₂₅ H₂₃ O₄ Cl, FW=422).

EXAMPLE 117 ##STR187##

Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77mmol) in diethyl ether (22 mL) at a rate to maintain reflux. Afteraddition, the mixture was heated at 40° C. for 2 h. The mixture wascooled and poured onto ice. The organic layer was separated and dilutedwith diethyl ether (100 mL), washed with saturated sodium bicarbonate(2×50 mL) and saturated sodium chloride (50 mL). The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo to afford1-phenyl-3-bromo-1-propyn (13.4 g, 90%).

The general method of Example 108 was used to prepare Example 117 using,as stated, 1-phenyl-3-bromo-1-propyn with 0.9 eq of Nal, instead of5-phenyl-1-iodopentane in Step 3, as indicated below. ##STR188##

EXAMPLE 117

From 1-phenyl-3-bromo-1-propyn: MP 141°-142° C.; ¹ H NMR (DMSO-d₆) δ12.50 (s, 1H, COOH), 8.08 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H),7.78 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.34 (m, 5H), 3.59 (dd,J=19.0, 10.3 Hz, 1H, CH₂ CO), 3.30 (m, 1H, CH₂ CO), 3.16 (m, 1H,CHCOOH), 2.81 (d, J=6.2 Hz, 2H, CH₂ CH); ¹³ C NMR (DMSO-d₆) δ 197.59,174.46, 143.26, 137.65, 135.42, 133.36, 131.29, 129.07, 128.78, 128.70,128.54, 128.16, 126.95, 122.78, 87.52, 82.25, 40.34, 38.95, 22.40; MS(FAB-HRMS) 403.1101 (M+H)⁺ (C₂₅ H₂₀ O₃ Cl, FW=403.1 112). ##STR189##

EXAMPLE 118

Methods similar to those of Chem. Pharm. Bull. 36(6), 2050-2060, (1988)were used to prepare Example 118 as follows:

In a 250 mL round bottom flask, 9.84 g (32.77 mmol) of Example 30 wasdissolved in 48 mL of DMF. The flask was placed under Ar. Thiopivalicacid (8.4 mL, 66.09 mmol, 2eq) was added to the flask via syringefollowed by addition of 3.2 mL of a 1.93M solution of K₂ CO₃ in H₂ O.The mixture was then stirred at 25° C. for 23 hours.

The reaction was diluted with 200 mL H₂ O and acidified with 10% HCl topH=1. The mixture was extracted with ethyl acetate (100 mL, ×3). Thecombined organic extracts were washed with water (100 mL, ×4), driedover magnesium sulfate and concentrated in vacuo to yield crude product(13.16 g, 96% crude).

The crude material was dissolved in ethanol, treated with activatedcarbon, filtered and concentrated in vacuo. The residue wasrecrystallized from ethyl acetate and hexane to yield 11.2 g (81%) ofwhite crystals. (Example 118).

MP: 119°-120° C.; TLC (methylene chloride-5%methanol) R_(f) 0.280; ¹ HNMR (CDCl₃) δ 8.03 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.84 Hz, 2H), 7.56 (d,J=8.84 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 3.51 (m, 1H), 3.28 (m, 4H), 1.24(s, 9H); ¹³ C NMR (CDCl₃) δ 206.75, 197.48, 179.28, 145.42, 138.87,135.89, 135.18, 129.81, 129.46, 129.17, 127.78, 47.22, 41.15, 39.49,29.91, 27.97; MS (FAB-LSIMS) 419 M+H!⁺ (C₂₂ H₂₃ SO₄ Cl, FW=418.94);Anal. C: calcd, 63.07; found, 62.96. H: calcd, 5.53; found, 5.47. Cl:calcd, 8.46; found, 8.50. S: calcd, 7.65; found 7.37.

EXAMPLE 119 and EXAMPLE 120

Example 118 (1.38 g injected in several portions) was separated bychromatography on a Chiralcel® OJ HPLC column (2 cm×25 cm) using 9ml/min. 85% hexane/15% (0.2% trifluoroacetic acid in ethanol) and peakdetection by UV at 320 nM. The best fractions of each isomer werecombined and each material was then recrystallized from ethylacetate/hexane to yield 520 mg of pure Example 119 (first to elute) and504 mg of pure Example 120 (second to elute).

EXAMPLE 119

MP 117°-118° C.; α!D +26.4 (CHCl₃); ¹ H NMR essentially identical tothat of Example 118.

EXAMPLE 120

MP 117°-118° C.; α!D -27.0 (CHCl₃); ¹ H NMR essentially identical tothat of Example 118.

Other ThioMichael Products

The following thioMichael material was made by a similar method to thatused for Example 118 except that the indicated thiol-containingcompounds was used instead of thiopivalic acid. ##STR190##

EXAMPLE 121

From thiophenol: MP: 125°-126° C.; TLC (methylene chloride--5% methanol)R_(f) 0.254; ¹ H NMR (CDCL₃) δ 8.01 (d, J=8.84 Hz, 2H), 7.64 (d, J=8.60Hz, 2H), 7.56 (d, J=8.84 Hz, 2H) 7.43 (m, 4H), 7.25 (m, 3H), 3.52 (m,3H), 3.33 (m, 1H), 3.19 (m, 1H); ¹³ C NMR (CDCL₃) δ 197.71, 179.25,145.46, 135.84, 135.48, 135.20, 130.64, 129.83, 129.44, 129.17, 127.78,127.44, 104.99, 40.83, 39.25, 35.68; MS (FAB-LSIMS) 411 M+H!⁺ (C₂₃ H₁₉SO₃ Cl, FW=410.92); Anal. C: calcd, 67.22; found, 66.94. H: calcd, 4.66;found, 4.70. Cl: calcd, 8.63; found, 8.81. S: calcd, 7.80; found 7.64##STR191##

EXAMPLE 122

Mother liquors from crystallization of crude Example 121 werechromatographed on silica gel to yield a purified sample of the isomericproduct Example 122.

¹ H NMR (DMSO-d6) δ 12.5 (bs,1 H), 7.4-8.0 (m, 8H), 3.5 (d, J=2.9 Hz,2H), 1.48 (s, 3H) ; ¹³ C NMR (CDCl₃) δ 197.19, 174.37, 144.46, 138.66,138.26, 136.40, 134.51, 131.09, 130.90, 130.15, 129.98, 129.86, 129.67,128.00, 52.46, 47.63, 23.60; MS (FAB-LSIMS) 411 M+H!⁺ (C₂₃ H₁₉ SO₃ Cl,FW=410.92); Anal. C: calcd, 67.23; found, 66.92. H: calcd, 4.66; found,4.66. Cl: calcd, 8.63; found, 8.72. S: calcd, 7.80; found 7.69

Resolution of Example 121 EXAMPLE 123

A solution of Example 121 (24 g, 0.058 mol) and (+)-cinchonine (10 g,0.034 mol) in acetone (150 mL) was allowed to stand at room temperaturefor 46 h. The white precipitate was removed by filtration, suspended inethyl acetate and washed successively with 2N HCl (150 mL) and sat. aq.NaCl (100 mL). The organic layer was dried over MgSO₄, filtered andconcentrated under reduced pressure to give a white solid (8.4 g, isomerratio 95.3:4.7 (Example 123:Example 124)). A second iteration(Cinchonine, 6.75 g; acetone, 140 mL) followed by simple crystallizationwith an ethyl acetate/hexanes mixture (1:2) provided Example 123 (6.67g, 56% theoretical; isomer ratio 99.3:0.7) as a white crystalline solid.

HPLC conditions for Example 121 (Example 123 and Example 124)

column: Chiralcel® AD analytical column

flow rate: 1 mL/min

solvent system: 10% (ethanol; 1% water; 0.2% TFA) in hexanes

detection: I=288

concentration: 0.5 mg/mL

injection amount: 4 μL

39.7 min. (Example 123); 44.6 min. (Example 124)

EXAMPLE 123

MP 110°-110.5° C., α!D +84.8° (c 1.5, acetone); ¹ H NMR (CDCl₃) δ 8.01(dt, J₁ =8.4 Hz, J₂ =1.8 Hz, 2 H), 7.69 (dt, J₁ =8.4 Hz, J₂ =1.8 Hz, 2H), 7.56 (dt, J₁ =8.7 Hz, J₂ =2.4 Hz, 2 H), 7.45 (m, 4 H), 7.29 (m, 2H), 7.20 (tt, J₁ =6.9 Hz, J₂ =1.5 Hz, 1 H), 3.51 (m, 3 H), 3.34 (m, 1H), 3.19 (dd, J₁ =13.5 Hz, J₂ =8.4 Hz, 1 H); ¹³ C NMR (CDCl₃) δ 197.0,178.7, 144.8, 138.2, 135.2, 134.8, 134.5, 129.9, 129.1, 129.0, 128.7,128.5, 127.0, 126.7, 40.2, 38.5, 35.0; MS (FAB) m/z (relative intensity)411 (M⁺ +H, 100), 393 (40), 215 (40). Anal. Calcd for C₂₃ H₁₉ O₃ ClS: C,67.23; H, 4.66; Cl, 8.63; S, 7.80. Found C, 67.00; H, 4.75; Cl, 8.79; S,7.58.

EXAMPLE 124

Purified samples of this isomer could be obtained by HPLC on aChiralpak® AD column (2 cm×25 cm) using ethanol/hexane (1:9.+0.15%trifluoroacetic acid added to the ethanol). With these conditionsExample 124 eluted second and could be obtained pure only from verysmall injections. Use of a proprietary chiral stationary phase accordingto the general procedures of: D. ArIt, B. Boemer, R. Grosser and W.Lange, Angew. Chem. Int. Ed. Engl. 30 (1991) No. 12, pages 1662-1664yielded larger quantities of pure material with isomer ratio <1:>99. Thebest chromatograpy fractions were freed of solvent by evaporation invacuo and then the residue (830 mg)was recrystallized from ethylacetate/hexane mixture to yield pure material (479 mg).

MP 108°-109° C.; α!D -79.8° (c 1.0, acetone); ¹ H NMR; ¹³ C NMR and MSessentially identical to that of Example 123; Anal. Calcd for C₂₃ H₁₉ O₃ClS: C, 67.23; H, 4.66; Cl, 8.63; S, 7.80; found C, 67.10; H, 4.65; Cl,8.54; S, 7.72.

EXAMPLE 125, EXAMPLE 126, EXAMPLE 127 and EXAMPLE 128

A sample of Example 121 was stored for several days as a solution in amixed solvent containing tetrahydrofuran which also containedsignificant quantities of peroxides. This resulted in the formation ofsignificant quantities of the isomeric sulfoxides Example 125, Example126, Example 127 and Example 128 which were separated into purefractions by chromatography on chiral HPLC stationary phases. These samecompounds can also be isolated from aged samples of Example 121 or itsisomers Example 123 or Example 124 or samples of the same materials insolution with added hydrogen peroxide. The two sulfoxides Example 127and Example 128 are often found as contaminants in aged air oxidizedsamples of Example 123 and therefore must share the C-2 stereochemistryof Example 123, but differ in the stereochemistry at the sulfoxideoxygen. Likewise Example 125 and Example 126 are found in aged samplesof Example 124 and therefore share the C-2 stereochemistry of Example124, but differ in stereochemistry at sulfoxide. ##STR192##

EXAMPLE 125

MP 151°-152° C.; TLC (methylene chloride--10% methanol) R_(f) 0.290; α!D-99.7 (c 0.6, acetone), ¹ H NMR (DMSO-d₆) δ 12.68 (bs, 1H), 8.05 (d,J=8.45 Hz, 2H), 7.85 (d, J=8.46 Hz, 2H), 7.79 (d, J=8.82 Hz, 2H), 7.70(m, 2H), 7.57 (m, 5H), 3.38 (m, 5H); ¹³ C NMR (DMSO-d₆) δ 197.12,173.88, 143.88, 143.31, 137.61, 135.25, 133.36, 131.02, 129.34, 129.05,128.79, 128.66, 126.92, 124.01, 57.44, 35.36; MS (FAB-LSIMS) 427 M+H!⁺(C₂₃ H₁₉ O₄ SCl, FW=426.92); Anal. C: calcd, 64.71; found, 63.44. H:calcd, 4.49; found, 4.40. Cl: calcd, 8.30; found, 8.17. S: calcd, 7.51;found, 7.35. ##STR193##

EXAMPLE 126

MP 146.5°-147.5° C.; TLC (methylene chloride--10% methanol) R_(f) 0.290;α!D +100.6 (c 0.6, acetone); ¹ H NMR (DMSO-d₆) δ 12.71 (bs, 1 H), 7.97(d, J=8.46 Hz, 2H), 7.78 (m, 4H), 7.68 (m,2H), 7.54(m, 5H), 3.51 (m, 1H)3.31 (m, 3H), 2.97 (m, 1H); ¹³ C NMR (DMSO-d₆) δ 196.98, 173.98, 144.70,143.29, 135.17, 133.36, 130.97, 129.34, 129.05, 128.77, 128.65, 126.88,123.85, 57.96, 39.63, 35.02; MS (FAB-LSIMS) 427 M+H!⁺ (C₂₃ H₁₉ O₄ SCl,FW=426.92); Anal. C: calcd, 64.71; found, 64.40. H: calcd, 4.49; found,4.47. Cl: calcd, 8.30; found, 8.19. S: calcd, 7.51; found, 7.34.##STR194##

EXAMPLE 127

MP 146°-147° C.; TLC (methylene chloride-10% methanol) R_(f) 0.303; α!D-97.4 (c 0.6, acetone); ¹ H NMR (DMSO-d₆) δ 12.71 (bs, 1H), 7.98 (d,J=8.46 Hz, 2H), 7.79 (m, 4H), 7.69 (m,2H), 7.56(m, 5H), 3.50 (m, 1H)3.33 (m, 3H), 2.98 (m, 1H); ¹³ C NMR (DMSO-d₆) δ 196.97, 173.96, 144.70,143.29, 137.61, 135.17, 133.36, 130.97, 129.34, 129.05, 128.79, 128.64,126.88, 123.85, 57.94, 39.63, 35.03; MS (FAB-LSIMS) 427 M+H!⁺ (C₂₃ H₁₉O₄ SCl, FW=426.92); Anal. C: calcd, 64.71; found, 64.61. H: calcd, 4.49;found, 4.36. Cl: calcd, 8.30; found, 8.27. S: calcd, 7.51; found, 7.36.##STR195##

EXAMPLE 128

MP 144°-145° C.; TLC (methylene chloride--10% methanol) R_(f) 0.303; α!D+95.6 (c 0.6, acetone); ¹ H NMR (DMSO-d₆) δ 12.66 (bs, 1H), 8.04 (d,J=8.82 Hz, 2H), 7.84 (d, J=8.47 Hz, 2H), 7.78 (d, J=8.83 Hz, 2H), 7.69(m, 2H), 7.56(m, 5H), 3.38 (m, 5H); ¹³ C NMR (DMSO-d₆) δ 197.12, 143.88,143.31, 135.25, 131.02, 129.34, 129.05, 128.79, 128.66, 126.92, 124.01,119.14, 57.44, 38.85, 35.36; MS (FAB-LSIMS) 427 M+H!⁺ (C₂₃ H₁₉ O₄ SCl,FW=426.92); Anal. C: calcd, 64.71; found, 64.32. H: calcd, 4.49; found,4.35. Cl: calcd, 8.30; found, 8.12. S: calcd, 7.51; found, 7.35.##STR196##

EXAMPLE 129

From 2-mercaptothiophene: MP: 136°-137° C.; TLC (methylene chloride--5%methanol) R_(f) 0.289; ¹ H NMR (CDCl₃) δ 8.03 (d, J=8.6 Hz, 2H), 7.65(d, J=8.6 Hz, 2H), 7.56 (d, J=8.84 Hz, 2H), 7.44 (d, J=8.84 Hz, 2H),7.36 (m, 1H), 7.17 (m, 1H), 6.97(m, 1H), 3.54 (m, 2H), 3.31 (m, 2H),3.06 (m, 1H); ¹³ C NMR (CDCl₃) δ 197.59, 179.71, 145.47, 138.84, 135.85,135.27, 135.21, 133.38, 130.78, 129.83, 129.47 129.18, 128.43, 127.79,40.85, 40.44, 39.02; MS (FAB-LSIMS) 417 M+H!⁺ (C₂₁ H₁₇ S₂ O₃ Cl,FW=416.94); Anal. C: calcd, 60.49; found, 60.28. H: calcd, 4.11; found,4.04. Cl: calcd, 8.50; found, 8.39. S: calcd, 15.37; found 14.98.##STR197##

EXAMPLE 130

From thiolacetic acid: MP: 140°-141° C.; TLC (methylene chloride--5%methanol) R_(f) 0.228; ¹ H NMR (CDCl₃) δ 8.03 (d, J=8.6 Hz, 2H), 7.65(d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 3.40(m, 5H), 2.36 (s, 3H); ¹³ C NMR (CDCl₃) δ 197.41, 195.86, 179.23,145.48, 138.84, 135.81, 135.19, 129.83, 129.47, 129.17, 127.81, 41.07,39.44, 31.20, 30.44; MS (FAB-LSIMS) 377 M+H!⁺ (C₁₉ H₁₇ SO₄ Cl,FW=376.87); Anal. C: calcd, 60.56; found, 60.42. H: calcd, 4.55; found,4.49. Cl: calcd, 9.41; found, 9.45. S: calcd, 8.51; found 8.27.##STR198##

EXAMPLE 131

From 4-methoxybenzylmercaptan: MP 126°-127° C.; TLC (methylenechloride--10% methanol) R_(f) 0.392; ¹ H NMR (CDCl₃) δ 8.02 (d, J=8.45Hz, 2H), 7.66 (d, J=8.45 Hz, 2H), 7.56 (d, J=8.82 Hz, 2H), 7.45 (d,J=8.82 Hz, 2H), 7.24 (d, J=8.46 Hz, 2H), 6.84 (d, J=8.83 Hz, 2H), 3.78(s, 3H), 3.71 (s, 2H), 3.44 (m, 2H), 3.31 (m, 1H), 2.93 (m, 1H), 2.69(m, 1H); ¹³ C NMR (CDCl₃) δ 197.29, 177.55, 158.74, 144.80, 138.19,135.21, 134.54, 130.02, 129.64, 129.15, 128.81, 128.50, 127.09, 113.99,55.23, 39.81, 38.99, 35.89, 32.42; MS (FAB-LSIMS) 455 M+H!⁺ (C₂₅ H₂₃ SO₄Cl, FW=454.97); Anal. C: calcd, 65.99; found, 66.04. H: calcd, 5.09;found, 5.04. Cl: calcd, 7.79; found, 7.94. S: calcd, 7.04; found, 6.95##STR199##

EXAMPLE 132

From thiolbenzoic acid. Treated with decolorizing carbon andrecrystallized from Ethyl Acetate and Hexane:

MP 162°-164° C.; TLC (methylene chloride--5% methanol) R_(f) 0.262; ¹ HNMR (CDCl₃) δ 8.00 (m, 4H), 7.54 (m, 8H), 3.52 (m, 5H); ¹³ C NMR (CDCl₃)δ 197.21, 190.64, 174.20, 143.26, 137.65, 136.18, 135.33, 134.03,133.36, 129.12, 129.07, 128.81, 128.71, 126.89, 29.68; MS (FAB-LSIMS)439 M+H!⁺ (C₂₄ H₁₉ O₄ SCl, FW=438.93); Anal. C: calcd, 65.68; found,65.40. H: calcd, 4.36; found, 4.27. Cl: calcd, 8.07; found, 7.74. S:calcd, 7.30; found, 7.06. ##STR200##

EXAMPLE 133

From benzyl mercaptan. Recrystallized from Ethyl Acetate and Hexane:

MP 155°-157° C.; TLC (methylene chloride--5% methanol) R_(f) 0.260; ¹ HNMR (CDCl₃) δ 8.04 (m, 2H), 7.57 (m, 6H), 7.31 (m, 5H), 3.75 (s, 2H),3.40 (m, 3H), 2.95 (m, 1H), 2.72 (m, 1H); ¹³ C NMR (CDCl₃) δ 197.12,178.86, 144.76, 138.19, 137.71, 135.22, 134.51, 129.15, 128.94, 128.81,128.60, 128.50, 127.19, 127.08, 39.97, 38.94, 36.48, 32.51; MS(FAB-LSIMS) 425 M+H!⁺ (C₂₄ H₂₁ O₃ SCl, FW=424.95); Anal. C: calcd,67.84; found, 67.71. H: calcd, 4.98; found, 4.85. Cl: calcd, 8.34;found, 8.32. S: calcd, 7.54; found, 7.64. ##STR201##

EXAMPLE 134

From 4-hydroxythiophenol. Recrystallized twice from Ethyl Acetate andHexane:

MP 162°-163° C.; TLC (methylene chloride--10% methanol) R_(f) 0.429; ¹ HNMR (MeOH-d₄) δ 8.00 (d, J=8.46 Hz, 2H), 7.70 (m, 4H), 7.47 (d, J=8.46Hz, 2H), 7.30 (d, J=8.83 Hz, 2H), 6.72 (d, J=8.83 Hz, 2H), 3.27 (m, 5H);¹³ C NMR (MeOH-d₄) δ 199.53, 158.61, 145.72, 136.94, 135.31, 130.15,129.83, 129.73, 128.07, 125.16, 117.17, 42.09, 40.12, 38.73; MS(FAB-LSIMS) 427 M+H!⁺ (C₂₃ H₁₉ O₄ SCl, FW=426.92); Anal. C: calcd,64.71; found, 64.63. H: calcd, 4.49; found, 4.65. Cl: calcd, 8.30;found, 8.28. S: calcd, 7.51; found, 7.38. ##STR202##

EXAMPLE 135

From 2-phenylethylmercaptan. Chromatographed over silica gel with 2%Methanol and Methylene Chloride and recrystallized from Ethyl Acetateand Hexane:

MP 105°-106° C.; TLC (methylene chloride--10% methanol) R_(f) 0.574; ¹ HNMR (CDCl₃) δ 8.04 (d, J=8.46 Hz, 2H), 7.65 (d, J=8.09 Hz, 2H), 7.55 (d,J=8.08 Hz, 2H), 7.44 (d, J=8.09 Hz, 2H), 7.25 (m, 5H), 3.42 (m, 3H),2.87 (m, 6H); ¹³ C NMR (CDCl₃) δ 197.14, 178.99, 144.78, 140.11, 138.18,135.25, 134.53, 129.15, 128.86, 128.81, 128.50, 128.47, 127.11, 126.42,40.28, 38.82, 35.98, 33.86, 33.35; MS (FAB-LSIMS) 439 M+H!⁺ (C₂₅ H₂₃ O₃SCl, FW=438.97); Anal. C: calcd, 68.40; found, 67.93. H: calcd, 5.28;found, 5.26. Cl: calcd, 8.08; found, 8.29. S: calcd, 7.30; found, 7.38.##STR203##

EXAMPLE 136

From 4-methoxythiophenol. Recrystallized from Ethyl Acetate and Hexane.Note: the second crop of crystals contained the product:

MP 138°-139° C.; TLC (methylene chloride--10% methanol) R_(f) 0.529; ¹ HNMR (CDCl₃) δ 8.00 (d, J=8.46 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.56 (d,J=8.46 Hz, 2H), 7.45 (d, J=8.82 Hz, 2H), 7.38 (d, J=8.82 Hz, 2H), 6.82(d, J=8.83 Hz, 2H), 3.76 (s, 3H), 3.39 (m, 4H), 3.09 (m, 1 H); ¹³ C NMR(CDCl₃) δ 197.06, 178.94, 159.33, 144.72, 138.19, 134.51, 133.77,129.15, 128.76, 128.49, 127.05, 124.87, 114.79, 55.26, 40.24, 38.45,37.03; MS (FAB-LSIMS) 441 M+H!⁺ (C₂₄ H₂₁ O₄ SCl, FW=440.95); Anal. C:calcd, 65.38; found, 65.23. H: calcd, 4.80; found, 4.76. Cl: calcd,8.04; found, 8.21. S: calcd, 7.27; found, 7.15. ##STR204##

EXAMPLE 137

From 3-phenylpropane-1-thiol. Purified by HPLC (100% CH₂ CL₂ on silica)then recrystallized from ethyl acetate and hexane, then Purified byreverse phase HPLC (methanol and water) and finally recrystallized fromethyl acetate and hexane:

MP 82°-83° C.; TLC (methylene chloride--10% methanol) R_(f) 0.50; ¹ HNMR (CDCl₃) δ 8.05 (d, J=8.46 Hz, 2H), 7.65 (d, J=8.09 Hz, 2H), 7.56 (d,J=8.46 Hz, 2H), 7.45 (d, J=8.46 Hz, 2H), 7.22 (m, 5H), 3.34 (m, 3H),3.01 (m, 1H), 2.76 (m, 3H), 2.57 (m, 2H), 1.94 (m, 2H); ¹³ C NMR (CDCl₃)δ 197.25, 178.02, 144.81, 141.26, 138.18, 135.25, 134.53, 129.15,128.79, 128.50, 128.43, 128.39, 127.13, 125.93, 40.15, 38.85, 34.65,33.23, 31.75, 30.86; MS (FAB-LSIMS) 453 M+H!⁺ (C₂₆ H₂₅ O₃ SCl,FW=452.00). ##STR205##

EXAMPLE 138

From 4-fluorothiophenol. Recrystallized twice from ethyl acetate andhexane then from 1-chlorobutane:

MP 112°-113° C.; TLC (methylene chloride--10% methanol) R_(f) 0.519; ¹ HNMR (CDCl₃) δ 7.99 (d, J=8.46 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.55 (d,J=8.45 Hz, 2H), 7.42 (m, 4H), 6.98 (m, 2H), 3.36 (m, 5H); ¹³ C NMR(CDCl₃) δ 196.86, 178.58, 163.81, 144.89, 138.16, 134.57, 133.22,133.10, 129.18, 128.76, 128.50, 127.13, 116.45, 116.16, 40.19, 38.52,36.32; MS (FAB-LSIMS) 429 M+H!⁺ (C₂₃ H₁₈ O₃ SFCl, FW=428.91); Anal. C:calcd, 64.41; found, 64.33. H: calcd, 4.23; found, 4.20. Cl: calcd,8.27; found, 8.58. S: calcd, 7.47; found, 7.54. F: calcd, 4.43; found,4.50. ##STR206##

EXAMPLE 139

From 4-chlorothiophenol. Recrystallized twice from ethyl acetate andhexane then from 1-chlorobutane:

MP 152°-153° C.; TLC (methylene chloride--10% methanol) R_(f) 0.558; ¹ HNMR (CDCl₃) δ 7.98 (d, J=8.09 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.55 (d,J=8.09 Hz, 2H), 7.44 (d, J=8.45 Hz, 2H), 7.32 (d, J=8.46 Hz, 2H), 7.23(d, J=8.83 Hz, 2H), 3.38 (m, 5H); ¹³ C NMR (CDCl₃) δ 196.79, 178.44,144.93, 138.14, 135.06, 134.57, 131.41, 129.28, 129.16, 128.74, 128.52,127.13, 40.18, 38.48, 35.17; MS (FAB-LSIMS) 445 M+H!⁺ (C₂₃ H₁₈ O₃ SCl ,FW=445.36); Anal. C: calcd, 62.03; found, 61.83. H: calcd, 4.07; found,3.86. Cl: calcd, 15.92; found, 15.83. S: calcd, 7.20; found, 7.31.##STR207##

EXAMPLE 140

From 4-bromothiophenol. Recrystallized from ethyl acetate and hexane:

MP 153°-154° C.; TLC (methylene chloride--10% methanol) R_(f) 0.519; ¹ HNMR (CDCl₃) δ 7.98 (d, J=8.46 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.56 (d,J=8.46 Hz, 2H), 7.45 (d, J=8.46 Hz, 2H), 7.38 (d, J=8.45 Hz, 2H), 7.25(d, J=8.46 Hz, 2H), 3.38 (m, 5H); ¹³ C NMR (CDCl₃) δ 196.79, 178.42,138.14, 135.04, 134.57, 134.15, 132.20, 131.52, 129.16, 128.74, 128.52,127.13, 120.73, 40.18, 38.48, 34.95; MS (FAB-LSIMS) 491 M+H!⁺ (C₂₃ H₁₈O₃ SBrCl, FW=489.82); Anal. C: calcd, 56.40; found, 56.43. H: calcd,3.70; found, 3.51. Cl: calcd, 7.23 found, 7.23. S: calcd, 6.55; found,6.68. Br: calcd, 16.31; found, 16.10. ##STR208##

EXAMPLE 141

From 4-methylthiophenol. Recrystallized from ethyl acetate and hexane:

MP 125°-127° C.; TLC (methylene chloride--10% methanol) R_(f) 0.585; ¹ HNMR (CDCl₃) δ 7.99 (d J=8.83 Hz, 2H), 7.63 (d, J=8.45 Hz, 2H), 7.55 (d,J=8.83 Hz, 2H), 7.44 (d, J=8.82 Hz, 2H), 7.30 (d, J=8.08 Hz, 2H), 7.08(d, J=8.09 Hz, 2H), 3.47 (m, 3H), 3.28 (m, 1H), 3.13 (m, 1H), 2.82 (s,3H); ¹³ C NMR (CDCl₃) δ 197.06, 178.81, 144.73, 138.21, 137.06, 135.20,134.53, 131.00, 130.83, 129.94, 129.16, 128.78, 128.50, 127.06, 40.21,38.48, 35.72, 21.02; MS (FAB-LSIMS) 425 M+H!⁺ (C₂₄ H₂₁ O₃ SCl,FW=424.95); Anal. C: calcd, 67.84; found, 67.75. H: calcd, 4.98; found,4.89. Cl: calcd, 8.34; found, 8.34. S: calcd, 7.54; found, 7.61.##STR209##

EXAMPLE 142

From 4-ethylthiophenol. Recrystallized twice from ethyl acetate andhexane:

MP 122°-123° C.; TLC (methylene chloride--10% methanol) R_(f) 0.547; ¹ HNMR (CDCl₃) δ 7.99 (d J=8.46 Hz, 2H), 7.63 (d, J=8.45 Hz, 2H), 7.55 (d,J=8.46 Hz, 2H), 7.44 (d, J=8.46 Hz, 2H), 7.33 (d, J=8.46 Hz, 2H), 7.12(d, J=8.09 Hz, 2H), 3.48 (m, 3H), 3.30 (m, 1H), 3.14 (m, 1H), 2.59 (q,J=7.60 Hz, 2H), 1.19 (t, J=7.71 Hz, 3H); ¹³ C NMR (CDCl₃) δ 197.00,179.23, 144.70, 143.32, 138.18, 135.19, 134.48, 131.26, 130.71, 129.13,128.74, 128.47, 127.03, 40.28, 38.47, 35.59, 28.34, 15.37; MS(FAB-LSIMS) 439 M+H!⁺ (C₂₅ H₂₃ O₃ SCl, FW=438.99); Anal. C: calcd,68.40; found, 68.33. H: calcd, 5.28; found, 5.17. Cl: calcd, 8.08;found, 7.91. S: calcd, 7.30; found, 7.26. ##STR210##

EXAMPLE 143

From 4-tert-butylthiophenol. Recrystallized twice from ethyl acetate andhexane:

MP 135°-136° C.; TLC (methylene chloride--10% methanol) R_(f) 0.547; ¹ HNMR (CDCl₃) δ 7.99 (d J=8.46 Hz, 2H), 7.63 (d, J=8.46 Hz, 2H), 7.54 (d,J=8.45 Hz, 2H), 7.44 (d, J=8.46 Hz, 2H), 7.32 (m, 4H), 3.49 (m, 2H),3.31 (m, 1H), 3.14 (m, 1H), 1.28 (s, 9H); ¹³ C NMR (CDCl₃) δ 197.04,179.21, 150.11, 144.73, 138.19, 135.20, 134.51, 131.22, 130.12, 129.15,128.74, 128.49, 127.06, 126.22, 40.34, 38.53, 35.33, 34.46, 31.20; MS(FAB-LSIMS) 467 M+H!⁺ (C₂₇ H₂₇ O₃ SCl, FW=467.03); Anal. C: calcd,69.44; found, 68.64. H: calcd, 5.83; found, 5.63. Cl: calcd, 7.59;found, 7.44. S: calcd, 6.86; found, 6.99. ##STR211##

EXAMPLE 144

From cyclohexylmercaptan. Recrystallized from ethyl acetate and hexane,and the filtrate was purified by reverse phase HPLC (75% Methanol, 25%Water, and 0.05% TFA).

TLC (methylene chloride--10% methanol) R_(f) 0.640; ¹ H NMR (CDCl₃) δ8.05 (d J=8.45 Hz, 2H), 7.65 (d, J=8.09 Hz, 2H), 7.55 (d, J=8.82 Hz,2H), 7.44 (d, J=8.46 Hz, 2H), 3.40 (m, 3H), 3.06 (m, 1H), 2.75 (m, 2H),1.80 (m, 5H), 1.33 (m, 5H); MS (FAB-LSIMS) 417 M+H!⁺ (C₂₃ H₂₅ O₃ SCl,FW=416.97); ##STR212##

EXAMPLE 145

From 3,4-dimethoxythiophenol. Recrystallized twice from 1-chlorobutane:

MP 144°-145° C.; TLC (methylene chloride--10% methanol) R_(f) 0.467; ¹ HNMR (CDCl₃) δ 7.99 (d, J=8.46 Hz, 2H), 7.63 (d, J=8.45 Hz, 2H), 7.55 (d,J=8.45 Hz, 2H), 7.44 (d, J=8.82 Hz, 2H), 6.99 (m, 2H), 6.75 (d, J=8.09Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.41 (m, 4H), 3.13 (m, 1H); ¹³ CNMR (CDCl₃) δ 197.04, 178.55, 149.21, 144.79, 134.55, 129.16, 128.73,128.50, 127.06, 125.30, 124.67, 114.98, 111.63, 55.94. 55.87, 40.31,38.48, 36.72; MS (FAB-LSIMS) 471 M+H!⁺ (C₂₅ H₂₃ SO₅ Cl, FW=470.98);Anal. C: calcd, 63.75; found, 63.74. H: calcd, 4.92; found, 4.84. Cl:calcd, 7.53; found, 7.47. S: calcd, 6.81; found 6.81. ##STR213##

EXAMPLE 146

From 3,4-dichlorothiophenol. Recrystallized from 1-chlorobutane thenethyl acetate and hexane:

MP 156°-157° C.; TLC (methylene chloride--10% methanol) R_(f) 0.545; ¹ HNMR (CDCl₃) δ 7.99 (d J=8.46 Hz, 2H), 7.65(d, J=8.46 Hz, 2H), 7.56 (d,J=8.83 Hz, 2H), 7.45 (m, 3H), 7.32 (m, 1 H), 7.22 (m, 1 H), 3.41 (m,5H); ¹³ C NMR (CDCl₃) δ 196.59, 178.66, 144.99, 138.13, 135.43, 134.93,134.59, 133.07, 131.13, 130.79, 129.18, 128.86, 128.71, 128.53, 127.15,40.23, 38.40, 34.74; MS (FAB-LSIMS) 479 M+H!⁺ (C₂₃ H₁₇ O₃ SCl ,FW=479.81); Anal. C: calcd, 57.58; found, 57.49. H: calcd, 3.57; found,3.49. Cl: calcd, 22.17; found, 21.91. S: calcd, 6.68; found, 6.79.##STR214##

EXAMPLE 147

From 2-mercaptobenzyl alcohol. Recrystallized from 1-chlorobutane thenethyl acetate and hexane, then 1-chlorobutane:

MP 111°-112° C.; TLC (methylene chloride--10% methanol) R_(f) 0.457; ¹ HNMR (CDCl₃) δ 7.98 (d, J=8.46 Hz, 2H), 7.63(d, J=8.46 Hz, 2H), 7.54 (d,J=8.82 Hz, 2H), 7.44 (m, 4H), 7.25 (m, 2H), 5.40 (bs, 1H), 4.80(m, 2H).3.42 (m, 5H); ¹³ C NMR (CDCl₃) δ 196.96, 177.82, 144.86, 141.31, 138.11135.08, 134.56, 133.38, 131.25, 129.15, 128.95, 128.78, 128.63, 128.49,127.52, 127.11, 63.52, 40.31, 38.90, 35.87; MS (FAB-LSIMS) 441 M+H!⁺(C₂₄ H₂₁ SO₄ Cl, FW=440.95); Anal. C: calcd, 65.38; found, 65.22. H:calcd, 4.80; found, 4.68. Cl: calcd, 8.04; found, 8.16. S: calcd, 7.27found 7.22. ##STR215##

EXAMPLE 148

From 2-fluorothiophenol. Recrystallized from ethyl acetate and hexane.

MP 131°-132° C.; TLC (methylene chloride--10% methanol) R_(f) 0.491; ¹ HNMR (CDCl₃) δ 8.02 (d, J=8.45 Hz, 2H), 7.64 (d, J=8.09 Hz, 2H), 7.55 (d,J=8.45 Hz, 2H), 7.44 (m, 3H), 7.15 (m, 3H), 3.49 (m, 3H), 3.21 (m, 2H);¹³ C NMR (CDCl₃) δ 231.29, 197.00, 177.97, 144.85, 135.16, 133.15,129.44, 129.34, 129.16, 128.79, 128.50, 127.11, 124.74, 124.69, 116.08.115.79, 40.18, 38.52, 34.74; MS (FAB-LSIMS) 429 M+H!⁺ (C₂₃ H₁₈ SO₃ ClF,FW=428.91); Anal. C: calcd, 64.41; found, 64.48. H: calcd, 4.23; found,4.20. Cl: calcd, 8.27; found, 8.11. S: calcd, 7.47; found 7.30.##STR216##

EXAMPLE 149

From 2-bromothiophenol. Recrystallized from ethyl acetate and hexane:

MP 159°-160° C.; TLC (methylene chloride--10% methanol) R_(f) 0.477; ¹ HNMR (CDCl₃) δ 8.05 (d, J=8.46 Hz, 2H), 7.66 (d, J=8.46 Hz, 2H), 7.57 (m,3H), 7.45 (m, 3H), 7.31 (m, 1H), 7.07 (m, 1H), 3.56 (m, 3H), 3.37 (m,1H), 3.25 (m, 1H); ¹³ C NMR (CDCl₃) δ 196.95, 178.60, 144.87, 138.16,136.24, 135.11, 133.24, 129.34, 129.17, 128.81, 128.50, 128.07, 127.52,127.13, 124.48, 39.80, 38.71, 34.22; MS (FAB-LSIMS) 490 M+H!⁺ (C₂₃ H₁₈SO₃ ClBr, FW=489.92); Anal. C: calcd, 56.40; found, 56.34. H: calcd,3.70; found, 3.65. Br: calcd, 16.31; found, 16.22. Cl: calcd, 7.23;found, 7.11. S: calcd, 6.54; found 6.33. ##STR217##

EXAMPLE 150

From 2-ethylthiophenol. Recrystallized from ethyl acetate and hexane:

MP 134°-135° C.; TLC (methylene chloride--10% methanol) R_(f) 0.504; ¹ HNMR (CDCl₃) δ 8.00 (d, J=8.45 Hz, 2H), 7.64 (d, J=8.82 Hz, 2H), 7.55 (dJ=8.82 Hz, 2H), 7.42 (m 3H), 7.16 (m, 3H), 3.44 (m, 4H), 3.17 (m, 1H),2.77 (q, J=7.47 Hz, 2H), 1.20 (t, J=7.54 Hz, 3H); ¹³ C NMR (CDCl₃) δ197.04, 178.37, 138.19, 135.20, 134.54, 133.57, 129.47, 129.16, 128.77,128.50, 127.11, 126.82, 126.68, 119.59, 40.09, 38.73, 34.85, 26.94,14.79; MS (FAB-LSIMS) 439 M+H!⁺ (C₂₅ H₂₃ SO₃ Cl, FW=438.97); Anal. C:calcd, 68.40 found, 68.37. H: calcd, 5.28; found, 5.21. Cl: calcd, 8.08;found, 7.90. S: calcd, 7.30; found 7.58. ##STR218##

EXAMPLE 151

From 2-isopropylthiophenol. Recrystallized from ethyl acetate andhexane:

MP 149°-150° C.; TLC (methylene chloride--10% methanol) R_(f) 0.531; ¹ HNMR (CDCl₃) δ 8.01 (d, J=8.09 Hz, 2H), 7.64 (d, J=8.09 Hz, 2H), 7.55 (d,J=8.46 Hz, 2H), 7.42 (m, 3H), 7.19 (m, 3H), 3.43 (m, 5H), 3.16 (m, 1H),1.21 (d, J=6.62 Hz, 6H); ¹³ C NMR (CDCl₃) δ 197.00, 178.62, 148.98,144.79, 138.19, 135.21, 134.53, 132.93, 130.05, 129.15, 128.77, 128.50,127.19, 127.09, 126.50, 125.81, 40.08, 38.69, 35.38, 30.26, 23.51,23.39; MS (FAB-LSIMS) 453 M+H!⁺ (C₂₆ H₂₅ SO₃ Cl, FW=453.00); Anal. C:calcd, 68.93; found, 68.94. H: calcd, 5.56; found, 5.54. Cl: calcd,7.82; found, 7.82. S: calcd, 7.07; found 6.90. ##STR219##

EXAMPLE 152

From 4-mercaptopyridine. Prepared in a manner similar to Example 121 butit was the aqueous layer that was neutralized with 1N NaOH to pH=4 andthe solid that formed was collected and recrystallized from ethylacetate.

MP 190°-191° C.; TLC (methylene chloride--20% methanol) R_(f) 0.613; ¹ HNMR (DMSO-d₆) δ 12.69 (bs, 1H), 8.38 (d, J=6.25 Hz, 2H), 8.04 (d, J=8.45Hz, 2H), 7.81 (m, 4H), 7.56 (d, J=8.82 Hz, 2H), 7.33 (d, J=6.25 Hz, 2H),3.56 (m, 1H), 3.36 (m, 3H), 3.18 (m, 1H); ¹³ C NMR (DMSO-d₆) δ 197.33,174.14, 149.29, 147.77, 143.33, 137.61, 135.25, 133.38, 129.07, 128.79,128.71, 126.92, 120.64, 39.71, 39.40, 31.25; MS (FAB-LSIMS) 412 M+H!⁺(C₂₂ H₁₈ SNO₃ Cl, FW=411.91); Anal. C: calcd, 64.15; found, 63.49. H:calcd, 4.40; found, 4.45. N: calcd, 3.40; found, 3.29. Cl: calcd, 8.61;found, 8.67. S: calcd, 7.78; found 7.86. ##STR220##

EXAMPLE 153

From N-acetyl-4-mercaptoaniline. Recrystallized from ethyl acetate andhexane then 1-chlorobutane, what did not dissolve in the 1-chlorobutanewas filtered and this was the product.

MP 165°-166° C. then 203°-204° C.; TLC (methylene chloride--10%methanol) R_(f) 0.370; ¹ H NMR (DMSO-d₆) δ 12.50 (bs, 1H), 9.97 (bs,1H), 7.99 (d, J=8.08 Hz, 2H), 7.79 (m, 4H), 7.55 (m, 4H), 7.33 (d,J=8.46 Hz, 2H), 3.35 (m, 3H), 3.11 (m, 2H), 2.00 (s, 3H); ¹³ C NMR(DMSO-d₆) δ 197.48, 174.37, 168.28, 143.23, 138.16, 133.35, 130.63,129.07, 128.79, 128.65, 126.87, 119.60, 23.96; MS (FAB-LSIMS) 468M+H!+(C₂₅ H₂₂ SNO₄ Cl, FW=467.98); Anal. C: calcd, 64.16; found, 63.97.H: calcd, 4.74; found, 4.64. N: calcd, 2.99; found, 2.98. Cl: calcd,7.58; found, 7.42. S: calcd, 6.85; found 6.92. ##STR221##

EXAMPLE 154

From 4-nitrothiophenol. Recrystallized from Ethyl Acetate and Hexane:

MP 211°-212° C.; TLC (methylene chloride--10% methanol) R_(f) 0.550; ¹ HNMR (DMSO-d₆) δ 12.69 (bs, 1H), 8.13 (d, J=8.83 Hz, 2H), 8.03 (d, J=8.46Hz, 2H), 7.80 (m, 4H), 7.56 (m, 4H), 3.37 (m, 5H) ; ¹³ C NMR (DMSO-d₆) δ197.25, 174.09, 146.72, 144.62, 143,33, 137.59, 135.20, 133.38, 129.05,128.77, 128.69, 126.88, 126.66, 123.96, 39.69, 32.56; MS (FAB-LSIMS) 456M+H!⁺ (C₂₃ H₁₈ SNO₅ Cl, FW=455.92); Anal. C: calcd, 60.59; found, 60.26.H: calcd, 3.98; found, 3.86. N: calcd, 3.07; found, 2.98. Cl: calcd,7.77; found, 7.61. S: calcd, 7.03; found 6.90. ##STR222##

EXAMPLE 155

From 3-(4-mercaptophenyl)propionic acid. Recrystallized from1-chlorobutane:

MP 172°-173° C.; TLC (methylene chloride--10% methanol) R_(f) 0.30; ¹ HNMR (DMSO-d₆) δ 12.32 (s, 1H), 7.99 (d, J=8.46 Hz, 2H), 7.79 (m, 4H),7.55 (d, J=8.45 Hz, 2H), 7.29 (d, J=8.45, 2H), 7.18 (d, J=8.09 Hz, 2H),3.49 (m, 1H), 3.31 (m, 4H), 3.11 (m, 2H), 3.76 (m, 2H); ¹³ C NMR(DMSO-d₆) δ 197.48, 174.35, 173.71, 143.26, 139.13, 137.64, 135.32,133.36, 132.59, 129.11, 129.07, 128.81, 128.66, 126.90, 40.15, 39.06,35.01, 34.62, 29.78; MS (FAB-LSIMS) 483 M+H!⁺ (C₂₆ H₂₃ SO₅ Cl,FW=482.99; Anal. C: calcd, 64.66; found, 64.46. H: calcd, 4.80 found,4.65. Cl: calcd, 7.34; found, 7.11. S: calcd, 6.63; found 6.55.##STR223##

EXAMPLE 156

From 2-mercaptonaphthaline. Recrystallized from ethyl acetate andhexane, then 1-chlorobutane:

MP 155°-156° C.; TLC (methylene chloride--10% methanol) R_(f) 0.489; ¹ HNMR (CDCl₃) δ 7.93 (d, J=8.45 Hz, 2H), 7.83 (m, 1H), 7.73 (m, 2H), 7.49(m, 10H), 3.55 (m ,3H), 3.33 (m, 2H); 13C NMR ((CDCl₃) δ 197.11, 178.62,144.87, 138.32, 135.21, 134.67, 132.14, 129.29, 128.95, 128.84, 128.65,128.28, 127.82, 127.71, 127.37, 127.15, 126.77, 126.11, 40.45, 38.65,34.84; MS (FAB-LSIMS) 461 M+H!⁺ (C₂₇ H₂₁ SO₃ Cl, FW=460.98); Anal. C:calcd, 70.35; found, 70.17. H: calcd, 4.59; found, 4.46. Cl: calcd,7.69; found, 7.71. S: calcd, 6.95; found 6.80. ##STR224##

EXAMPLE 157

From 1-mercaptonaphthaline. Recrystallized from ethyl acetate andhexane, then 1-chlorobutane.

MP 168°-169° C.; TLC (methylene chloride--10% methanol) R_(f) 0.50; ¹ HNMR (CDCl₃) δ 8.41 (m, 1H), 7.65 (m 14H), 3.51 (m, 3H), 3.30 (m, 2H); ¹³C NMR (CDCl₃) δ 178.18, 150.54, 144.72, 138.18, 135.09, 134.51, 134.03,133.08, 132.04, 129.59, 129.15, 128.71, 128.68, 128.48, 128.11, 127.03,126.69, 126.31, 125.61, 124.93, 40.25, 38.62, 35.66; MS (FAB-LSIMS) 461M+H!⁺ (C₂₇ H₂₁ SO₃ Cl, FW=460.98); Anal. C: calcd, 70.35; found, 70.31.H: calcd, 4.59; found, 4.43. Cl: calcd, 7.69; found, 7.63. S: calcd,6.95; found 6.86. ##STR225##

EXAMPLE 158

From 3-bromothiophenol. Recrystallized from ethyl acetate and hexane:

MP 167°-168° C.; TLC (methylene chloride--10% methanol) R_(f) 0.450; ¹ HNMR (DMSO-d₆) δ 12.61 (bs 1H), 8.02 (d, J=8.46 Hz, 2H), 7.79 (m, 4H),7.55 (m, 3H), 7.37 (m, 2H), 7.26 (m, 1H), 3.33 (m, 5H); ¹³ C NMR(DMSO-d₆) δ 197.33, 174.21, 138.63, 137.61, 135.24, 133.35, 130.94,129.92, 129.05, 128.78, 128.66, 126.98, 126.87, 122.28, 39.95, 33.72; MS(FAB-LSIMS) 491 M+H!⁺ (C₂₃ H₁₈ SO₃ ClBr, FW=489.92); Anal. C: calcd,56.40; found, 56.35. H: calcd, 3.70; found, 3.67. Cl: calcd, 7.24;found, 7.39. S: calcd, 6.55; found, 6.39. Br: calcd, 16.31; found,16.38. ##STR226##

EXAMPLE 159

From 2-methoxythiophenol. Recrystallized from ethyl acetate and hexane,then 1-chlorobutane:

MP 115°-116° C.; TLC (methylene chloride--10% methanol) R_(f) 0.452 ¹ HNMR (CDCl₃) δ 7.99 (d, J=8.09, 2H), 7.54 (m, 6H), 7.19 (m, 1H), 6.96 (m,2H), 6.72 (m,1H), 3.77 (s, 3H), 3.47 (m, 4H), 3.22 (m 1H); ¹³ C NMR(CDCl₃) δ 196.94, 179.02, 159.93, 144.75, 138.18, 136.16, 135.15,134.51, 129.97, 129.15, 128.76, 128.47, 127.06, 121.75, 114.82, 112.53,55.26, 40.26, 38.53, 34.64; MS (FAB-LSIMS) 441 M+H!⁺ (C₂₄ H₂₁ SO₄ Cl,FW=440.95); Anal. C: calcd, 65.38; found, 65.19. H: calcd, 4.80; found,4.81. Cl: calcd, 8.04; found, 8.02. S: calcd, 7.27; found 7.02.##STR227##

EXAMPLE 160

From 2-chlorothiophenol. Recrystallized from ethyl acetate and hexane:

MP 153°-154° C.; TLC (methylene chloride--10% methanol) R_(f) 0.533; ¹ HNMR (CDCl₃) δ 8.03 (m, 2H), 7.65 (m, 2H), 7.55 (m, 2H) 7.44 (m, 3H),7.37 (m, 1H), 7.24 (m, 1H) 7.14 (m, 1H), 3.53 (m, 3H), 3.33 (m, 1H),3.21 (m, 1H); ¹³ C NMR (CDCl₃) δ 196.99, 178.19, 138.18, 135.12, 134.57,134.41, 129.97, 129.77, 129.18, 128.83, 128.52, 127.50, 127.45, 127.15,39.84, 38.71, 33.83; MS (FAB-LSIMS) 445 M+H!⁺ (C₂₃ H₁₈ SO₃ Cl₂,FW=445.36); Anal. C: calcd, 62.03; found, 61.87. H: calcd, 4.07; found,4.16. Cl: calcd, 15.92; found, 16.21. S: calcd, 7.19; found 7.12.##STR228##

EXAMPLE 161

From 3-methylthiophenol. Recrystallized from ethyl acetate and hexane:

MP 137°-138° C.; TLC (methylene chloride--10% methanol) R_(f) 0.525; ¹ HNMR (CDCl₃) δ 7.99 (d, J=8.83 Hz, 2H), 7.63 (d, J=8.45 Hz, 2H), 7.55 (d,J=8.82 Hz, 2H), 7.44 (d, J=8.83 Hz, 2H), 7.18 (m, 3H), 6.98 (m, 1H) 3.49(m, 4H), 3.18 (m, 1H), 2.29 (m, 3H); ¹³ C NMR (CDCl₃) δ 196.99, 179.09,144.75, 138.97, 138.19, 135.19, 134.59, 134.51, 130.49, 129.15, 128.99,128.76, 128.49, 127.58, 127.06, 126.87, 40.26, 38.52, 34.89, 21.28; MS(FAB-LSIMS) 425 M+H!⁺ (C₂₄ H₂₁ SO₃ Cl, FW=424.95); Anal. C: calcd,67.84; found, 67.76. H: calcd, 4.98; found, 4.81. Cl: calcd, 8.34;found, 8.48. S: calcd, 7.54; found 7.40. ##STR229##

EXAMPLE 162

From 2-methylthiophenol. Recrystallized from ethyl acetate and hexane:

MP 130°-131° C.; TLC (methylene chloride--10% methanol) R_(f) 0.551; ¹ HNMR (CDCl₃) δ 8.01(d, J=8.46 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.55 (d,J=8.82 Hz, 2H), 7.44 (d, J=8.83 Hz, 2H), 7.37 (m, 1H), 7.14 (m, 3H),3.47 (m, 4H), 3.16 (m, 1H), 2.39 (s, 3H) ; ¹³ C NMR (CDCl₃) δ 196.99,178.60, 144.78, 138.24, 138.18, 135.19, 134.09, 130.38, 129.15 129.07,128.76, 128.49, 127.09, 126.66, 126.55, 40.06, 38.69, 34.28, 20.44; MS(FAB-LSIMS) 425 M+H!⁺ (C₂₄ H₂₁ SO₃ Cl, FW=424.95); Anal. C: calcd, 67.84; found, 67.56. H: calcd, 4.98; found, 5.06. Cl calcd, 8.34; found,8.45. S: calcd, 7.54; found 7.40. ##STR230##

EXAMPLE 163

From 2-mercaptobenzoic acid. Recrystallized from ethyl acetate andhexane:

MP 221°-222° C.; TLC (methylene chloride--15% methanol+0.5% acetic acid)R_(f) 0.441; ¹ H NMR (DMSO-d₆) δ 12.75 (bs, 1.5H), 8.062 (d, J=7.36 Hz,2H), 7.84 (m, 5H), 7.55 (m, 4H), 7.25 (m, 1H), 3.59, (m, 1H), 3.29 (m,4H); ¹³ C NMR (DMSO-d₆) δ 197.47, 174.39, 167.45, 143.28, 139.86,137.64, 135.32, 133.36, 132.41, 130.97, 129.06, 128.79, 128.71, 128.66,126.91, 125.67, 124.22, 39.40, 32.79; MS (FAB-LSIMS) 455 M+H!⁺ (C₂₄ H₁₉SO₅ Cl, FW=454.92); Anal. C: calcd, 63.37; found, 63.39. H: calcd, 4.21;found, 4.04. Cl: calcd, 7.79; found, 7.81. S: calcd, 7.05; found 7.06.##STR231##

EXAMPLE 164

From 3-methoxythiophenol. Recrystallized from ethyl acetate and hexane,then 1-chlorobutane the ethyl acetate and hexane.

MP 143°-144° C.; TLC (methylene chloride--10% methanol) R_(f) 0.828; ¹ HNMR (DMSO-d₆) δ 12.51 (bs, 1H), 8.02 (d, J=8.46 Hz, 2H), 7.80 (m, 4H),7.56 (d, J=8.83 Hz, 2H), 7.33 (m, 1 H), 7.20 (m, 1 H), 6.96 (m, 2H),3.78 (s, 3H), 3.37 (m, 5H); ¹³ C NMR (CDCl₃) δ 197.30, 178.32, 158.18,144.76, 135.29, 134.54, 131.75, 129.18, 128.83, 128.62, 128.53, 127.11,122.25, 121.25, 110.87, 55.80, 40.11, 38.74, 33.83; MS (FAB-LSIMS) 441M+H!⁺ (C₂₄ H₂₁ SO₄ Cl, FW=440.95); Anal. C: calcd, 65.38; found, 65.22.H: calcd, 4.80; found, 4.61. Cl: calcd, 8.04 found, 7.78. S: calcd,7.27; found 7.43. ##STR232##

EXAMPLE 165

From 3,5-dimethylthiophenol. Recrystallized from ethyl acetate andhexane:

MP 175°-176° C.; TLC (methylene chloride--10% methanol) R_(f) 0.482; ¹ HNMR (DMSO-d₆) δ 12.53 (bs, 1H), 8.01 (d, J=8.46 Hz, 2H), 7.79(m, 4H),7.55 (d, J=8.46 Hz, 2H), 6.97 (bs, 2H), 6.79 (bs, 1H), 3.51 (m, 1H),3.32 (m, 2H), 3.14 (m, 2H), 2.21 (bs, 6H); ¹³ C NMR (DMSO-d₆) δ 196.41,173.31, 142.25, 137.24, 136.61, 134.27, 134.12, 132.35, 128.05, 127.78,127.63, 126.63, 125.85, 124.97, 39.13, 38.05, 32.96, 19.75; MS(FAB-LSIMS) 439 M+H!⁺ (C₂₅ H₂₃ O₃ SCl, FW=438.97); Anal. C: calcd,68.40; found, 68.32. H: calcd, 5.28; found, 5.16. Cl: calcd, 8.08;found, 8.26. S: calcd, 7.30; found, 7.08. ##STR233##

EXAMPLE 166

From 3-trifluoromethythiophenol. Recrystallized from ethyl acetate andhexane.

MP 114°-115° C.; TLC (methylene chloride--10% methanol) R_(f) 0.517; ¹ HNMR (DMSO-d₆) δ 12.60 (bs, 1H), 8.00 (d, J=8.46 Hz, 2H), 7.79 (m, 4H),7.68 (m, 2H), 7.54 (m, 4H), 3.41 (m, 4H), 3.10 (m, 1H); ¹³ C NMR(DMSO-d₆) δ 197.31, 174.20, 143.31, 137.88, 137.63, 135.25, 133.36,131.81, 130.08, 129.07, 128.79, 128.68, 126.89, 124.05, 124.00, 122.45,39.94, 33.58; MS (FAB-LSIMS) 479 M+H!⁺ (C₂₄ H₁₈ O₃ SClF₃, FW=478.92);Anal. C: calcd, 60.19; found, 60.36. H: calcd, 3.79; found, 3.95. Cl:calcd, 7.40; found, 7.57. S: calcd, 6.69; found, 6.97. F: calcd, 11.90;found, 11.90. ##STR234##

EXAMPLE 167

From 4-carbomethoxythiophenol. Chromatographed on silica gel usingmethanol/methylene chloride mixtures and then recrystallized from ethylacetate and hexane:

MP 152°-153° C.; TLC (methylene chloride--10% methanol) R_(f) 0.462; ¹ HNMR (CDCl₃) δ 8.00 (d, J=8.46 Hz, 2H), 7.93 (d, J=8.46 Hz, 2H),7.64 (d,J=8.46 Hz, 2H), 7.56 (d, J=8.83 Hz, 2H), 7.45 (d, J=8.46 Hz, 2H), 7.39(d, J=8.46 Hz, 2H), 3.87 (s, 3H), 3.46 (m, 5H); ¹³ C NMR (CDCl₃) δ196.73, 177.84, 166.58, 144.91, 142.07, 138.09, 135.01, 134.59, 130.17,129.16, 128.76, 128.50, 127.57, 127.39, 127.11, 52.08, 40.02, 38.59,33.25; MS (FAB-LSIMS) 469 M+H!⁺ (C₂₅ H₂₁ O₅ SCl, FW=468.96); Anal. C:calcd, 64.03; found, 62.16. H: calcd, 4.51; found, 4.65. Cl: calcd,7.56; found, 8.19. S: calcd, 6.84; found, 6.21. ##STR235##

EXAMPLE 168

From 2-(4-mercaptophenyl)acetic acid. Recrystallized from ethyl acetateand hexane:

MP 162°-163° C.; TLC (methylene chloride--20% methanol) R_(f) 0.618; ¹ HNMR (DMSO-d₆) δ 12.43 (bs, 1H), 7.99 (d, J=8.83 Hz, 2H), 7.78 (m, 4H),7.54 (d, J=8.82 Hz, 2H), 7.32 (d, J=8.09 Hz, 2H), 7.20 (d, J=8.09 Hz,2H), 3.52 (m 3H), 3.31 (m, 2H), 3.12 (m, 2H); ¹³ C NMR (DMSO-d₆) δ197.46, 174.33, 172.57, 143.28, 137.66, 133.51, 133.36, 133.12, 130.25,129.08, 128.81, 128.71, 128.68, 126.92, 40.13, 39.58, 39.13, 38.68; MS(FAB-LSIMS) 469 M+H!⁺ (C₂₅ H₂₁ O₅ SCl, FW=468.96); Anal. C: calcd,64.03; found, 63.94. H: calcd, 4.51; found, 4.37. Cl: calcd, 7.56;found, 7.34. S: calcd, 6.84; found, 6.67. ##STR236##

EXAMPLE 169

From isopropylthiol. Purified by reverse phase HPLC using MeOH (75%)/H₂O (35%) and TFA (0.05%). The final product was recrystallized from ethylacetate and hexane.

MP 110°-111° C.; TLC (methylene chloride--10% methanol) R_(f) 0.561; ¹ HNMR (CDCl₃) δ 8.07 (d, J=8.82 Hz, 2H), 7.67 (d, J=8.46 Hz, 2H), 7.56 (d,J=8.46 Hz, 2H), 7.45 (d, J=8.46 Hz, 2H), 3.43 (m, 3H), 3.00 (m, 2H),2.83 (m, 1H), 1.29 (m, 6H); ¹³ C NMR (CDCl₃) δ 197.38, 177.66, 144.80,138.21, 135.29, 134.54, 129.17, 128.83, 128.52, 127.12, 40.35, 38.97,35.30, 31.74, 23.26; MS (FAB-LSIMS) 377 M+H!⁺ (C₂₀ H₂₁ O₃ SCl,FW=376.90). ##STR237##

EXAMPLE 170

From 2-hydroxythiophenol. Recrystallized from ethyl acetate and hexane:

MP 148°-149° C.; TLC (methylene chloride--10% methanol) R_(f) 0.448; ¹ HNMR (CDCl₃) δ 7.99 (d, J=8.83 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.55 (d,J=8.46 Hz, 2H), 7.46 (m, 3H), 7.26 (m, 1H), 6.98 (m, 1H), 6.86 (m, 1H),6.75 (bs, 1H), 3.55 (m, 1H), 3.20 (m, 4H); ¹³ C NMR (CDCl₃) δ 196.56,178.21, 156.93, 144.93, 138.11, 135.93, 134.99, 134.57, 131.52, 129.16,128.78, 128.49, 127.13, 121.04, 117.96, 115.39, 40.39, 38.84, 37.60; MS(FAB-LSIMS) 427 M+H!⁺ (C₂₃ H₁₉ O₄ SCl, FW=426.92); Anal. C: calcd,64.71; found, 64.47. H: calcd, 4.49; found, 4.60. S: calcd, 7.51; found,7.57. Cl: calcd, 8.30; found, 8.31. ##STR238##

EXAMPLE 171

From 8-mercaptoquinoline. Recrystallized from ethyl acetate and hexane:

MP 172°-173° C.; TLC (methylene chloride--10% methanol) R_(f) 0.518; ¹ HNMR (CDCl₃) δ 8.99 (m, 1H), 8.22 (m, 1H), 7.99 (d, J=8.83 Hz, 2H), 7.86(m, 1H), 7.72 (m, 1H), 7.50 (m, 8H), 3.69 (m, 1H), 3.41 (m, 4H); ¹³ CNMR (CDCl₃) δ 197.11, 177.45, 149.53, 146.19, 144.59, 138.14, 137.45,135.29, 135.17, 134.41, 129.92, 129.07, 128.74, 128.44, 127.08, 126.98,126.55, 121.83, 40.34, 39.55, 34.56; MS (FAB-LSIMS) 462 M+H!⁺ (C₂₆ H₂₀NO₃ SCl, FW=461.97); Anal. C: calcd, 67.60; found, 67.40. H: calcd,4.36; found, 4.39. N: calcd, 3.03; found, 3.03. S: calcd, 6.94; found,7.04. Cl: calcd, 7.67; found, 7.35. ##STR239##

EXAMPLE 172

From 3-chlorothiophenol. Recrystallized from ethyl acetate and hexane:

MP 164°-165° C.; TLC (methylene chloride--10% methanol) R_(f) 0.450; ¹ HNMR (DMSO-d₆) δ 12.58 (bs, 1H), 8.01 (d, J=8.45 Hz, 2H), 7.79 (m, 4H),7.54 (d, J=8.83 Hz, 2H), 7.43 (m, 1H), 7.32 (m, 2H), 7.23 (m 1H), 3.30(m, 5H); ¹³ C NMR (DMSO-d₆) δ 197.36, 174.22, 143.30, 138.39, 137.63,135.27, 133.36, 130.70, 129.07, 128.79, 128.68, 127.15, 126.90, 126.60,125.77, 33.67; MS (FAB-LSIMS) 445 M+H!⁺ (C₂₃ H₁₈ O₃ SCl, FW=445.36);Anal. C: calcd, 62.03; found, 62.22. H: calcd, 4.07; found, 3.93. S:calcd, 7.19; found, 7.03. Cl: calcd, 15.92; found, 15.54. ##STR240##

EXAMPLE 173

From 3-fluorothiophenol. Recrystallized from ethyl acetate and hexane:

MP 135°-136° C.; TLC (methylene chloride--10% methanol) R_(f) 0.420; ¹ HNMR (CDCl₃) δ 8.01 (d, J=8.82 Hz, 2H), 7.65 (d, J=8.83 Hz, 2H), 7.56 (d,J=8.45 Hz, 2H), 7.45 (d, J=8.83 Hz, 2H), 7.18 (m, 3H), 6.88 (m, 1H),3.36 (m, 5H); ¹³ C NMR (CDCl₃) δ 196.77, 178.84, 135.08, 134.56, 130.49,130.38, 129.16, 128.74, 128.49, 127.11, 124.79, 124.74, 116.26, 115.95,113.66, 113.37, 40.13, 38.56, 34.41; MS (FAB-LSIMS) 429 M+H!⁺ (C₂₃ H₁₈O₃ SFCl, FW=428.91); Anal. C: calcd, 64.41; found, 64.48. H: calcd,4.23; found, 4.17. S: calcd, 7.47; found, 7.53. Cl: calcd, 8.27; found,8.15. F: calcd, 4.43; found, 4.53. ##STR241##

EXAMPLE 174

From methyl 2-mercaptobenzoate. Recrystallized from ethyl acetate andhexane:

MP 167°-168° C.; TLC (methylene chloride--10% methanol) R_(f) 0.510; ¹ HNMR (DMSO-d₆) δ 12.62 (bs, 1H), 8.05 (d, J=8.46 Hz, 2H), 7.83 (m, 5H),7.58 (m, 4H), 7.27 (m, 1H), 3.81 (s, 3H), 3.55 (m, 1H), 3.37 (m, 2H),3.21 (m, 2H); ¹³ C NMR (DMSO-d₆) δ 197.38, 174.30, 166.09, 143.26,139.61, 137.61, 135.28, 133.35, 132.75, 130.73, 129.05, 128.78, 128.68,127.87, 126.89, 126.18, 124.51, 52.09, 39.37, 32.9; MS (FAB-LSIMS) 469M+H!⁺ (C₂₅ H₂₁ SO₅ Cl, FW=468.96); Anal. C: calcd, 64.03; found, 64.07.H: calcd, 4.51; found, 4.44. Cl: calcd, 7.56; found, 7.52. S: calcd,6.84; found 6.54. ##STR242##

EXAMPLE 175

A solution of Example 174 (20.9 mg, 0.0445 mmol) in THF (1.5 mL) wascooled in a dry ice/acetone bath. The reaction vessel was sealed with arubber septum and methylamine gas was bubbled through for approximately1 minute. The reaction was allowed to warm to room temperature andstirred for several hours. Concentration under reduced pressure andrecrystallization from ethyl acetate and hexane provided Example 175 aswhite crystals.

MP 185°-186° C.; TLC (methylene chloride--10% methanol) R_(f) 0.288; ¹ HNMR (DMSO-d₆) δ 12.51 (bs, 1H), 8.22 (m, 1H), 8.03 (d, J=8.46 Hz, 2H),7.80 (m, 4H), 7.46 (m, 5H), 7.24 (m, 1H), 3.51 (m, 1H), 3.34 (m, 2H),3.10 (m, 2H), 2.69 (d, J=4.41 Hz, 3H); ¹³ C NMR (DMSO-d₆) δ 198.61,175.52, 169.19, 144.37, 138.76, 138.58, 136.45, 135.68, 134.47, 131.12,130.19, 129.91, 129.78, 129.06, 128.73, 128.02, 126.42, 35.19, 27.10; MS(FAB-LSIMS) 468 M+H!⁺ (C₂₅ H₂₂ O₄ SNCl, FW=467.98); Anal. C: calcd,64.17; found, 64.04. H: calcd, 4.74; found, 4.92. N: calcd, 2.99; found,2.88. S: calcd, 6.85; found, 6.75. Cl: calcd,7.58; found, 7.84.

EXAMPLE 176 ##STR243## EXAMPLE 176

In a 25 mL round bottom flask, 209.8 mg (0.732 mmol) of Example 34 wasdissolved in 5 mL of 1,4-Dioxane. The flask was placed under Ar.Thiophenol, 0.1 mL (0.934 mmol, 1.33 eq) was added to the flask viasyringe. The mixture was then stirred at 25° C. At 102 hours anadditional 0.1 mL of thiophenol was added via syringe. The mixturestirred for a total of 125 hours. The reaction was then concentrated invacuo and the residue was recrystallized from ethyl acetate and hexaneto yield 93.0 mg (32%) of white crystals (mp=168°-169° C.). (Ref. Chem.Pharm. Bull. 36(6), 2050-2060 (1988).

TLC (methylene chloride--10% methanol) R_(f) 0.377; ¹ H NMR (CDCl₃) δ8.01 (d, J=8.46 Hz, 2H), 7.51 (m, 11H), 4.26 (m, 1H), 3.69 (m, 1H), 3.45(m, 1H); ¹³ C NMR (DMSO-d₆) δ 196.07, 176.09, 144.99, 138.11, 134.85,134.57, 133.73, 132.01, 129.19, 129.16, 128.79, 128.48, 127.16, 45.10,40.87; MS (FAB-LSIMS) 397 M+H!⁺ (C₂₂ H₁₇ O₃ SCl, FW=396.89); Anal. C:calcd, 66.58; found, 66.37. H: calcd, 4.32; found, 4.33. Cl: calcd,8.93; found, 9.07. S: calcd, 8.08; found, 8.18. ##STR244##

EXAMPLE 177

Made in a manner similar to Example 176 but the crude yellow crystalswere dissolved in ethanol, treated with decolorizing carbon, filteredand concentrated in vacuo. The residue was recrystallized from ethylacetate and hexane to yield 148 mg (40%) of white crystals (mp=162°-164°C.).

TLC (methylene chloride--10% methanol) R_(f) 0.435; ¹ H NMR (CDCl₃) δ7.96 (d, J=8.09 Hz, 2H), 7.49 (m, 11H), 3.85 (m, 4H), 3.20 (m, 1H); ¹³ CNMR (CDCl₃) δ 195.99, 177.39, 144.93, 138.13, 137.14, 134.77, 134.57,129.21, 129.15, 128.78, 128.65, 128.50, 127.42, 127.13, 40.53, 40.02,36.39; MS (FAB-LSIMS) 411 M+H!⁺ (C₂₃ H₁₉ O₃ SCl, FW=410.92); Anal. C:calcd, 67.23; found, 67.07. H: calcd, 4.66; found, 4.70. Cl: calcd,8.63; found, 8.73. S: calcd, 7.80; found, 7.82. ##STR245##

EXAMPLE 178 (Reference)

This compound was prepared using a method similar to that used forExample 118 except that thiolacetic acid was used instead of thiopivalicacid and Example 31 was used instead of Example 30.

MP: 94.0°-95.0° C. ¹ H NMR (DMSO-d₆) δ 12.5 (bs, 1H), 7.8 (d, J=7 Hz,2H), 7.3 (d, J=7 Hz, 2H), 3.4-3.0 (m, 5H), 2.35 (s, 3H), 2.30 (s, 3H);¹³ C NMR (DMSO-d₆) δ 198.19, 195.96, 175.32, 144.82, 134.93, 130.38,129.10, 120.27, 31.59, 30.85, 22.26; MS (FAB-LSIMS) 281 M+H!⁺ (C₁₄ H₁₆O₄ S, FW=280.27); Anal. C: calcd, 59.98; found, 59.93. H: calcd, 5.75;found, 5.76; S: calcd, 8.51; found, 8.31. S: calcd, 11.44; found, 11.53.##STR246##

EXAMPLE 179

195.3 mg (0.650 mmole) of Example 25 and 120.9 mg 2-mercaptothiophenewere dissolved in 3 ml of distilled THF. The reaction was purged withargon and stirred at ambient temperature overnight. The volatilecomponents were removed in vacuo to give a crude solid that wasrecrystallized (EtOAc-hexane) to give 140.0 mg (52%) of Example 179.

MP: 160.0°-161.0° C. ¹ H NMR (CDCl₃) δ 7.77 (d, J=9 Hz, 2H), 7.7-7.4 (m,6H), 7.20 (dd, J=1.5 Hz, J=3.5 Hz, 1 H), 7.06 (dd, J=3.6 Hz, J=5 Hz,2H), 4.07 (m, 1H), 3.21 (dd, J=4 Hz, J=13 Hz, 1H), 3.11-2.91 (m, 2H),2.70 9dd, J=9 Hz, J=13 Hz, 1H); ¹³ C NMR (CDCl₃) δ 199.90, 177.65,145.48, 138.81, 135.94, 135.24, 135.06, 133.32, 131.24, 129.86, 129.83,129.17, 128.59, 127.86, 42.54, 41.54, 41.15, 34.66; MS (FAB-LSIMS) 417M+H!⁺ (C₂₁ H₁₇ O₃ S₂ Cl, FW=416.94); Anal. C: calcd, 60.50; found,60.41. H: calcd, 4.11; found, 4.03. S: calcd, 15.38; found, 15.28. Cl:calcd, 8.50; found, 8.57.

EXAMPLE 180, EXAMPLE 181, and EXAMPLE 182

These compounds were similarly prepared from Example 25 and themercapto-compounds described below (recrystallized from EtOAc-hexane)##STR247##

EXAMPLE 180

From thiopivalic acid. MP: 106.0°-107.5° C.; ¹ H NMR (CDCl₃) δ 8.17 (d,J=8 Hz, 2H), 7.69 (d, J=8 Hz, 2H), 7.57 (d, J=8 Hz, 2H), 7.45 (d, J=8Hz, 2H), 4.11 (m, 1H), 3.33 (dd, J=6 Hz, J=4 Hz, H), 3.03 (dd, J=10 Hz,J=17 Hz, 1H), 2.82 (dd, J=9 Hz, 14 Hz, 1H), 2.7 (dd, J=17 Hz, J=4 Hz);¹³ C NMR (CDCl₃) δ 206.21, 199.72, 177.42, 144.80, 138.26, 134.78,134.46, 129.47, 129.13, 128.50, 127.23, 46.57, 41.86, 34.82, 30.44,27.28; MS (FAB-LSIMS) 419 M+H!⁺ (C₂₂ H₂₃ O₄ SCl, FW=418.90); Anal. C:calcd, 63.08; found, 63.05. H: calcd, 5.53; found, 5.46. S: calcd, 7.65;found, 7.27. Cl: calcd, 8.46; found, 8.53. ##STR248##

EXAMPLE 181

From thiophenol. MP: 135.0°-136.0° C.; ¹ H NMR (CDCl₃) δ 7.85 (d, J=8Hz, 2H), 7.60-7.25 (m, 11H, 4.05 (m,1H); ¹³ C NMR (CDCl₃) δ 200.34,178.36, 145.46, 138.81, 135.32, 135.27, 135.22, 131.75, 129.86, 129.83,129.17, 127.93, 127.83, 42.41, 37.13,35.37; M S (FAB-LSIMS) 411 M+H!⁺(C₂₃ H₁₉ O₃ SCl, FW=410.88); Anal. C: calcd, 67.23; found, 66.87. H:calcd, 4.66 found, 4.67. S: calcd, 7.80; found, 7.57. Cl: calcd, 8.63;found, 8.81. ##STR249##

EXAMPLE 182 (Reference with respect to composition)

From thioacetic acid. MP: 118.0°-119.0° C.; ¹ H NMR (CDCl₃) δ 8.2 (d,J=9 Hz, 2H), 7.7 (d, J=9 Hz, 2H), 7.6 (d, J=9 Hz, 2H), 7.5 (d, J=9 Hz,2H), 4.1 (m, 1H), 3.4 (dd, J=5 Hz, J=14 Hz, 1H), 3.0 (dd, J=9 Hz, J=17Hz, 1H), 2.8 (dd, J=9 Hz, J=14 Hz, 1H), 2.7 (dd, J=4 Hz, J=17 Hz, 1H),2.35 (s, 3H); ¹³ C NMR (CDCl₃) δ 200.03, 196.03, 178.05, 145.59, 138.87,135.21, 130.14, 129.83, 129.18, 127.94, 42.65, 35.37, 31.58, 31.20; MS(FAB-LSIMS) 377 M+H!⁺ (C₁₉ H₁₇ O₄ SCl, FW=376.83); Anal. C: calcd,60.56; found, 60.63. H: calcd, 4.55 found, 4.53; S: calcd, 8.51; found,8.31. Cl: calcd, 9.41; found, 9.45. ##STR250##

EXAMPLE 183 (Reference)

This compound was prepared by a method similar to that used for Example118 except that thiolacetic acid was used instead of thiopivalic acidand Example 35 was used instead of Example 30.

EXAMPLE 183

MP: 91.0°-92.0° C.; ¹ H NMR (DMSO-d₆) δ 7.94 (d, J=9 Hz, 2H), 7.36 (d,J=9 Hz,2H), 7.05-6.95 (m, 4H), 4.75 (m, 1H), 3.5-3.7 (m, 2H), 2.4 (s,3H); MS (FAB-LSIMS) 378 M+H!⁺ (C₁₈ H₁₅ O₅ SCl, FW=378.80). ##STR251##

EXAMPLE 184

Example 34 (0.36 mmoles) was dissolved in 10 ml of 1,4-dioxane underargon at ambient temperature. 1.06 EQ of thiomorpholine was added to thesolution and within 5 minutes a precipitate began to form. Someadditional 1,4-dioxane was added to make the mixture easier to stir.Stirring continued overnight. The solid was removed by filtration anddried in vacuo to yield 129 mg of the free base form of Example 184 as asolid product.

The hydrochloride salt of the product was formed by suspending theinitial solid in EtOH and bubbling HCl gas into the suspension untilclear. Et₂ O was used to precipitate the salt which was collected byfiltration to give final product Example 184.

MS (FAB-LSIMS) 390 M+H!⁺ (C₂₀ H₂₁ O₃ NSCl₂, FW=426.41).

EXAMPLE 185 and EXAMPLE 186

These compounds were prepared in the same way as Example 184 except thatthe indicated amine was added instead of thiomorpholine. In each casethe initial products were converted to hydrochlorides as above beforeassay as inhibitors of MMPs. ##STR252##

EXAMPLE 185

From aminodiphenylmethane (benzhydrylamine). ¹ H NMR (DMSO-d₆) δ 7.3-8.1(m, 18H), 5.76 (m, 1H), 4.22 (m, 1HO, 3.78 (m, 2H); MS (FAB-LSIMS) 470M+H!⁺ (C₂₉ H₂₅ O₃ NCl₂, FW=506.49). ##STR253##

EXAMPLE 186

From 2,6-dimethylmorpholine: ¹ H NMR (DMSO-d₆) δ 11.4 (bs, 1H), 8.10 (d,J=9 Hz, 2H), 7.88 (d, J=9 Hz, 2H), 7.78 (d, J=9 Hz, 2H), 7.56 (d, J=9Hz, 2H), 4.64 (m, 1H), 4.1-2.7 (m, 8H), 1.14 (d, J=6 Hz, 6H); MS(FAB-LSIMS) 402 M+H!⁺ (C₂₂ H₂₅ O₄ NCl₂, FW=423.32).

EXAMPLE 187 ##STR254## Step 1

A solution of triphenyl phosphine (2.1 g, 7.9 mmol) in dry methylenechloride (16 mL) was added dropwise over 10 min to a stirred mixture ofN-bromosucccinimide (1.4 g, 7.9 mmol) in dry methylene chloride (23 mL)at -78° C. The reaction was kept in the dark and stirring was continueduntil all the N-bromosucccinimide had dissolved (10 min). A solution of2-(benzyloxy)ethanol in dry methylene chloride (10 mL) was addeddropwise. The cooling bath was removed and stirring was continued for 12h at rt. The organic layer was then concentrated in vacuo and passedthrough a silica plug with 1:1 hexane:methylene chloride to afford2-(benzyloxy)bromoethane (1.20 g, 85%).

Step 2

The general method of the preparation of 4-phenyl-1-iodobutane (seeExample 107 preparation--step 2) was used to prepare2-(benzyloxy)iodoethane using 2-(benzyloxy)bromoethane rather than4-phenyl-1-chlorobutane. ##STR255## Step 3--Preparation of Example 187

The general method of Example 108 was used to prepare Example 187 using2-(benzyloxy)iodoethane instead of 5-phenyl-1-iodopentane.

EXAMPLE 187

MP 99°-100° C.; ¹ H NMR (CDCl₃) δ COOH (not seen), 8.05 (d, J=8.5 Hz,2H), 7.63 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz,2H), 7.33 (m, 5H), 4.53 (s, 2H, CH₂ Ph), 3.66 (t, J=5.9 Hz, 2H, CH₂ CO),3.50 (dd, J=16.9, 7.0 Hz, 1H, CH₂ CO), 3.25 (m, 2H, CHCOOH, CH₂ CO),2.13 (m, 1H, CH₂ CH), 1.98 (m, 1H, CH₂ CH); ¹³ C NMR (CDCl₃) δ 197.56,178.68, 144.65, 138.24, 137.80, 135.40, 134.50, 129.15, 128.76, 128.50,128.45, 127.77, 127.74, 127.08, 73.17, 68.12, 40.20, 37.85, 31.38; MS(FAB-HRMS) 423.1363 (M+H)⁺ (C₂₅ H₂₄ O₄ Cl, FW=423.1366). ##STR256##

EXAMPLE 188

This compound were prepared using the general procedure of Example 87except that the indicated commercial malonate was used instead of ethyl2-carboethoxy-5-phenylpentanoate. From diethyl2-trimethylsilylmethylmalonate:

MP 134°-136° C.; ¹ H NMR (CDCl₃) δ 8.02 (dd, J=6.6 Hz and 1.9 Hz, 2H);7.65 (d, J=6.6 Hz, 2H); 7.56 (d, J=6.6 Hz, 2H); 7.45 (dd, J=6.6 Hz and1.9 Hz, 2H); 3.50 (m, 1H); 3.10 (m, 3H); 1.08 (dd, J=14.8 Hz and 7.2 Hz,1H); 0.80 (dd, J=14.6 Hz and 7.2 Hz, 1H); 0.09 (s, 9H); ¹³ C NMR (CDCl₃)δ 198.13, 183.06, 145.27, 138.92, 136.11, 135.14, 129.81, 129.38,129.17, 127.78,43.75, 37.00, 20.56, -0.40; MS (FAB-LSIMS) 375 M+H!⁺,(C₂₀ H₂₃ Cl O₃ Si, FW=374.9); Anal. C: calcd, 64.07; found, 64.12. H:calcd, 6.18; found, 6.14. Cl: calcd; 9.46, found; 9.47. ##STR257##

EXAMPLE 189

This compound was prepared using the general procedure of Example 87except that commercial dimethyl 2-(3-N-phthalimidopropyl)malonate wasused instead of ethyl 2-carboethoxy-5-phenylpentanoate. Also thefollowing procedures were used instead of the treatment of the crude oilwith NaOH in ethanol/water and successive steps. The substituted diester(product from steps 1,2, and the first half of 3) was dissolved in a 1:4solution of concentrated hydrochloric acid:glacial acetic acid in asealed vessel and heated to 110° C. for 18 h. After cooling, solvent wasremoved under reduce pressure. The resultant was concentrated fromhexanes (2×25 mL) and toluene (2×25 mL) affording a solid which waschromatographed on silica gel with 3% acetic acid/ethyl acetate.

MP 191°-192° C.; ¹ H NMR (CDCl₃ /DMSO) δ 7.73 (d, J=8.5 Hz , 2H); 7.56(m, 2H); 7.46 (m, 2H); 7.37 (d, J=8.3 Hz, 2H); 7.29 (m, 2H); 7.17 (d,J=8.8 Hz, 2H); 3.44 (m, 2H); 3.21 (dd, J=18.7 Hz and 9.3 Hz, 1H); 2.76(m, 2H); 1.48 (m, 4H); ¹³ C NMR (DMSO) δ 199.8, 177.20, 168.70, 144.70,138.68, 136.08, 134.69, 134.51, 132.45, 129.56, 129.15, 129.01, 127.47,123.61, 29.65, 26.78; MS (FAB-LSIMS) 475 M+H!⁺, (C₂₇ H₂₂ NCl O₅,FW=475.9).

EXAMPLE 190 ##STR258## Step 1

The bromomethylketone product from step 2 of the Example 87 preparationwas recrystallized from ethyl acetate. In a 50 mL round bottom flask,1.22 g (3.94 mmol) of this purified material was dissolved in 12 mL ofdimethoxyethane (DME). Sodium iodide, 618.9 mg (4.13 mmol, 1.05 eq) wasadded to the flask to yield solution 1.

In a separate flask, 1.00 g (4.34 mmol, 1.1 eq) of commercial diethyl(2-dimethylaminoethyl)malonate was dissolved in 4 mL of DME. Sodiumethoxide, 336 mg (4.69 mmol) was added to the flask to yield solution 2.

Solution 1 was added to solution 2 and the mixture stirred at 25° C. for1.5 hours. The reaction was concentrated in vacuo and the residuedissolved in chloroform. The chloroform was washed twice with a 10%solution of potassium carbonate and once with a solution of sodiumbisulfite. The organic layer was dried over magnesium sulfate, filteredand concentrated in vacuo. ##STR259## Step 2

The residue from step 1 was dissolved in 20 mL of a 1:1:1 mixture ofethanol/water/tetrahydrofuran and 6 mL of 1.0N NaOH was added. Themixture was refluxed for several days, diluted with water, acidifiedwith 10% HCl to pH=3 and condensed. ##STR260## Step 3--Preparation ofExample 190

The resultant solid was mixed with 100 mL of 1N HCl and refluxed for 8hours. The mixture was filtered and the solid was washed with hotethanol. The ethanol washes were concentrated and crystals werecollected. The filtrate was concentrated to dryness and recrystallizedfrom ethyl acetate to produce 15.6 mg (3.7%) of white crystals ofExample 190.

MP 207°-208° C.; ¹ H NMR (DMSO-d₆) δ 8.06 (d, J=8.46 Hz, 2H), 7.82 (m,4H), 7.56 (d, J=8.46 Hz, 2H); the rest of the signals are buried underthe DMSO and H₂ O peaks; MS (FAB-LSIMS) 360 M+H!⁺ (C₂₀ H₂₂ NO₃ Cl.HCl,FW=359.86+HCl); Anal. C: calcd, 60.61; found, 59.81. H: calcd, 5.85;found, 5.75. N: calcd, 3.53; found, 3.30. Cl: calcd, 17.89; found,17.48. ##STR261##

EXAMPLE 191

Example 191 was made in a manner similar to Example 190 except thatdiethyl 2-(2-diethylaminoethyl)malonate was used instead of diethyl(2-dimethylaminoethyl)malonate. The final product was first crystallizedfrom acetone and hexane and then from acetone to yield pure Example 191.

MP 185°-186° C.; ¹ H NMR (DMSO-d₆) δ 12.75 (bs, 1H), 10.25 (bs, 1H),8.07 (d, J=8.46 Hz, 2H), 7.85 (d, J=8.46 Hz, 2H), 7.79 (d, J=8.83 Hz,2H), 7.56 (d, J=8.46 Hz, 2H), 3.23 (m, 9H), 1.99 (m, 2H), 1.20 (t,J=7.17 Hz, 6H); ¹³ C NMR (DMSO-d₆) δ 197.59, 175.23, 143.29, 137.63,135.35, 133.39, 129.07, 128.81, 128.73, 126.89, 48.52, 46.14, 37.51,24.76, 8.45; MS (FAB-LSIMS) 388 M+H!⁺ (C₂₂ H₂₆ NO₃ Cl.HClFW=387.91+HCl); Anal. C: calcd, 62.27; found, 62.28. H: calcd, 6.41;found, 6.32. N: calcd, 3.30; found, 3.20. Cl: calcd, 16.71; found,16.84. ##STR262##

EXAMPLE 192

Example 192 was prepared in a manner similar to Example 190 except thatdiethyl 2-(3-diethylaminopropyl)malonate was used instead of diethyl(2-dimethylaminoethyl)malonate. The solid that precipitated after theacidification with HCl was chromatographed by reverse phase HPLC usingMeOH(65%)/H₂ O (35%) and TFA (0.05%).

¹ H NMR (CDCl₃) δ 11.13 (bs, 1H), 8.01 (d, J=8.09 Hz, 2H), 7.62 (d,J=8.09 Hz, 2H), 7.54 (d, J=8.46 Hz, 2H), 7.44 (d, J=8.45 Hz, 2H), 4.33(m, 4H), 3.50 (m, 1H), 3.16 (m, 8H), 1.83 (m, 4H), 1.34 (m, 6H); MS(FAB-LSIMS) 402 M+H!⁺ (C₂₃ H₂₈ NO₃ Cl.TFA, FW=401.93+TFA). ##STR263##

EXAMPLE 193

Example 193 was prepared in a manner similar to Example 190 except thatdiethyl 2-(3-methylthiopropyl)malonate was used instead of diethyl(2-dimethylaminoethyl)malonate. The crude diester intermediate was notwashed with base. It was chromatographed over silica gel using Hexaneand ethyl acetate. After the final acidification the product wasextracted into ethyl acetate and concentrated. The residue was dissolvedin 1,4-dioxane and refluxed to decarboxylate. The crude product was thenchromatographed over silica gel using ethyl acetate and acetic acid. Theproduct was recrystallized from ethyl acetate and hexane.

MP 134°-135° C.; TLC (methylene chloride-5% methanol) R_(f) 0.274; ¹ HNMR (CDCl₃) δ 8.04 (d, J=8.43 Hz, 2H), 7.66 (d, J=8.43 Hz, 2H), 7.56 (d,J=8.43 Hz, 2H), 7.45 (d, J=8.80 Hz, 2H), 3.51 (m, 1H), 3.13 (m, 2H),2.55 (m, 2H), 2.11 (s, 3H), 1.80 (m, 4H); ¹³ C NMR (CDCl₃) δ 197.35,179.83, 144.75, 135.32, 134.53, 129.15, 128.76, 128.50, 127.13, 40.29,39.63, 33.82, 30.83, 26.58, 15.49; MS (FAB-LSIMS) 377 M+H!⁺ (C₂₀ H₂₁ O₃SCl, FW=376.90); Anal. C: calcd, 63.74; found, 63.54. H: calcd, 5.62;found, 5.56. S: calcd, 8.51; found, 8.34. Cl: calcd, 9.41; found, 9.59.##STR264##

EXAMPLE 194

This compound was prepared using the general methods of Example 107except that commercial N-(2-bromoethyl)phthalimide was used instead of4-phenyl-1-iodobutane in step 3. Also the alternative hydrolysis anddecarboxylation procedure given for Example 189 was used instead oftreatment with NaOH and then acid followed by heating.

MP 209°-210° C.; ¹ H NMR (CDCl₃ /DMSO) δ 7.75 (d, J=8.5 Hz , 2H); 7.54(m, 2H); 7.46 (m, 2H); 7.37 (d, J=6.5 Hz, 2H); 7.30 (m, 2H); 7.16 (d,J=8.5 Hz, 2H); 3.55 (m, 2H); 3.26 (dd, J=17.8 Hz and 8.3 Hz, 1 H); 2.94(dd, J=17.6 Hz and 5.0 Hz, 1 H); 2.76 (m, 1 H); 1.87 (m, 1H); 1.70 (m,1H); ¹³ C NMR (DMSO) δ 197.76, 176.68, 168.59, 144.72, 138.66, 136.06,134.69, 134.50, 132.46, 129.56, 129.18, 128.99, 127.47, 123.63, 38.40,36.32, 30.67, 27.86; MS (FAB-LSIMS) 462 M+H!⁺, (C₂₆ H₁₉ NCl O₅,FW=461.9). ##STR265##

EXAMPLE 195

This compound was made using the general methods of Example 107 exceptthat 2-methoxyethoxymethyl chloride was used instead of4-phenyl-1-iodobutane in step 3.

MP 95°-97° C.; ¹ H NMR (DMSO) δ 8.02 (d, J=8.5 Hz , 2H); 7.77 (m, 4H);7.54 (d, J=8.5 Hz, 2H); 3.64 (m, 2H); 3.46 (m, 5H); 3.20 (s, 3H); 3.16(m, 2H); ¹³ C NMR (DMSO) δ 198.82, 175.24, 144.27, 138.76, 136.63,134.43, 130.17, 129.88, 129.75, 128.01, 72.22, 71.93, 70.82, 59.19,42.04, 38.18; MS (FAB-LSIMS) 377 M+H!⁺, (C₂₀ H₂₁ Cl O₅, FW=376.8).##STR266##

EXAMPLE 196

The general method of Example 108 was used to prepare Example 196 usingcommercially available benzylchloromethyl ether with 0.9 eq of Nal,instead of 5-phenyl-1-iodopentane in Step 3.

¹ H NMR (DMSO-d₆) δ 12.33 (s, 1H, COOH), 8.05 (d, J=7.3 Hz, 2H), 7.84(d, J=7.3 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.30(m, 5H), 4.49 (s, 2H, CH₂ Ph), 3.69 (m, 2H, CH₂ CO), 3.51 (m, 1H,CHCOOH), 3.18 (d, 2H, CH₂ CH); ¹³ C NMR (DMSO-d₆) δ 197.70, 174.20,143.18, 138.25, 137.70, 135.53, 133.36, 129.10, 128.81, 128.71, 128.24,127.44, 127.08, 126.92, 72.07, 70.18, 40.92, 38.67; MS (FAB-LSIMS) 409(M+H)⁺ (C₂₄ H₂₁ O₄ Cl, FW=408); Anal. C: calcd, 70.50; found, 70.73. H:calcd, 5.18; found, 5.14. ##STR267##

EXAMPLE 197

This compound was prepared by a similar method to that used for Example30, except that the indicated anhydride was used instead of itaconicanhydride. From 2,2-dimethylsuccinic anhydride:

MP 179°-180° C.; TLC (methylene chloride--10% methanol) R_(f) 0.571; ¹ HNMR (CDCl₃) δ 8.03 (d, J=8.8 Hz, 2 H), 7.65 (d, J=8.07 Hz, 2 H), 7.55(d, J=8.07 Hz, 2 H), 7.45 (d, J=8.07 Hz, 2 H), 3.35 (s, 2 H), 1.4 (s, 1H); ¹³ C NMR (CDCl₃) δ 197.64, 183.80, 145.17, 138.92, 136.42, 135.11,129.80, 129.33, 129.17, 127.71, 48.95, 40.62, 26.29; MS (FAB-LSIMS) 317M+H!⁺ (C₁₈ H₁₇ O₃ Cl, FW=316.79); Anal. C: calcd, 68.25; found, 68.03.H: calcd, 5.41; found, 5.42. Cl: calcd, 11.19; found, 11.18.

EXAMPLE 198 ##STR268## Step 1--Preparation of 2,3-Dimethyl succinicanhydride.

To the 2,3-dimethyl succinic acid (5.13 g, 35.1 mmol), was added acetylchloride (8.27 g, 7.49 mL, 105 mmol) at room temperature. The reactionmixture was refluxed at about 65° C. for 2 hrs. Workup consisted ofconcentration in vacuo, and drying in high vacuo. The desired product(4.95 g, with a little impurity of acetic acid) was obtained as a whitesolid.

¹ H-NMR (CDCl₃) δ isomer #1: 1.25 (d, 6H), 3.18-3.23 (m, 2H); isomer #2:1.36 (d, 6H), 2.71-2.77 (m, 2H). ##STR269## Step 2--Preparation ofExample 198.

Produced using the general method of Example 1 except that1,2-dichloroethane was used as solvent and the anhydride from step 1 wasused instead of dihydro-3-(2-methylpropyl)-2,5-furandione.

MP 157°-159° C.; TLC (1/1 (v/v) EtOAc/hexane) Rf=0.21; ¹ H-NMR (CDCl₃) δ8.04 (d, J=8.09 Hz, 2H), 7.62 (d, J=8.09 Hz, 2H), 7.55 (d, J=8.45 Hz,2H), 7.44 (d, J=8.45 Hz, 2H), 3.81-3.71 (m, 1H), 3.07-2.97 (m, 1H), 1.28(d, J=7.35 Hz, 3H), 1.21 (d, J=7.36 Hz, 3H); MS (FAB-LSIMS) 317 M+H!⁺(C₁₈ H₁₇ ClO₃, FW=316.77); Anal. C: calcd, 68.25; found, 68.22. H:calcd, 5.41; found, 5.24. ##STR270##

EXAMPLE 199

This compound was prepared in a similar manner to Example 1, except thatthe indicated anhydride was used instead ofdihydro-3-(2-methylpropyl)-2,5-furandione. Frommeso-2,3-dimethylsuccinic anhydride:

MP 165.0°-167.0° C.; TLC (1/1 (v/v) EtOAc/hexane) Rf=0.17; ¹ H NMR(CDCl₃) δ 8.07 (d, J=8.46 Hz, 2H), 7.68 (d, J=8.09 Hz, 2H), 7.57 (d,J=8.46, 2H), 7.45 (d, J=8.82, 2H), 3.77 (dq, J=7.35 Hz, J=8.09 Hz, 1H),3.02 (dq, J=6.98 Hz, J=8.08 Hz, 1H), 1.30 (d, J=7.35 Hz, 3H), 1.24 (d,J=6.98 Hz, 1H); IR (nujol) 1708.7, 1679.7, 1604.5 cm⁻¹ ; MS (FAB-LSIMS)317 M+H!⁺ (C₁₈ H₁₇ ClO₃, FW=316.77); Anal. C: calcd, 68.25; found,68.23. H: calcd, 5.41; found, 5.26.

EXAMPLE 200, EXAMPLE 201, AND EXAMPLE 202

These compounds were prepared in a similar manner to Example 1, exceptthat the indicated anhydrides were used instead ofdihydro-3-(2-methylpropyl)-2,5-furandione: ##STR271##

EXAMPLE 200

From trans-cyclohexane-1,2-dicarboxylic acid anhydride: MP 187°-188° C.;TLC (methylene chloride-5% methanol) R_(f) 0.236; ¹ H NMR (DMSO-d₆) δ12.17 (bs, 0.7 H), 8.06 (d, J=8.8 Hz, 2 H), 7.81 (d, J=8.8 Hz, 2 H),7.76 (d, J=8.8 Hz, 2 H), 7.55 (d, J=8.8 Hz, 2 H), 3.61 (m, 1 H), 2.66(m, 1 H), 2.07 (bd, 1 H), 1.90 (bd, 1 H), 1.73 (m, 2 H), 1.39 (m, 3 H),1.09 (m, 1 H); ¹³ C NMR (DMSO-d₆) δ 203.13, 177.18, 144.21, 138.87,135.79, 134.40, 130.16, 130.09, 129.91, 128.12, 46.98, 45.37, 30.61,29.80, 26.34, 26.03; MS (FAB-LSIMS) 343 M+H!⁺ (C₂₀ H₁₉ O₃ Cl, FW=342);Anal. C: calcd, 70.07; found, 69.61. H: calcd, 5.59; found, 5.61. Cl:calcd, 10.34; found, 10.10. ##STR272##

EXAMPLE 201

From cis-cyclohexane-1,2-dicarboxylic acid anhydride: MP 180°-181° C.;TLC (methylene chloride--5% methanol) R_(f) 0.267; ¹ H NMR (DMSO-d₆) δ12.02 (bs, 0.6 H), 7.94 (d, J=8.07 Hz, 2 H), 7.76 (t, J=8.8 Hz, 4 H),7.53 (d, J=8.06 Hz, 2 H), 3.94 (m, 1 H), 2.68 (m, 1 H), 2.03 (m, 1 H),1.79 (m, 3 H), 1.59 (m, 1 H), 1.26 (m, 3 H); ¹³ C NMR (DMSO-d₆) δ202.92, 176.06, 143.66, 138.92, 136.68, 134.32, 130.24, 130.14, 129.86,127.98, 44.32, 43.37, 27.86, 26.39, 25.07, 23.29; MS (FAB-LSIMS) M+H!⁺(C₂₀ H₁₉ O₃ Cl, FW=342); Anal. C: calcd, 70.07; found, 69.77. H: calcd,5.59; found, 5.58. Cl: calcd, 10.34; found, 10.27. ##STR273##

EXAMPLE 202

From phthalic anhydride: MP >230° C.; TLC (methylene chloride--5%methanol) R_(f) 0.138; ¹ H NMR (DMSO-d₆) δ 13.17 (bs), 7.71 (m); ¹³ CNMR (DMSO-d₆) δ 205.89, 130.93, 130.68, 130.63, 130.17, 129.89, 128.02,41.08, 40.99, 40.71, 40.68, 40.50, 40.42, 40.16, 40.13, 39.96; MS(FAB-LSIMS) 337 M+H!⁺ (C₂₀ H₁₃ O₃ Cl, FW=336.78); Anal. C: calcd, 71.33;found, 69.94. H: calcd, 3.89; found, 3.92. Cl: calcd, 10.53; found,11.09.

EXAMPLE 203 ##STR274## Step 1--Preparation ofcis-Cyclopentane-1,2-dicarboxylic anhydride.

To the trans-cyclopentane-1,2-dicarboxylic acid (1.16 g, 7.33 mmol) atroom temperature, was added Acetic anhydride (10 mL, ex). The reactionmixture was refluxed at about 165° C. for 14 hrs. Workup consisted ofconcentration in vacuo and co-evaporation with toluene three times. Thecrude product (1.0 g, ˜100%, with a little impurity of Acetic anhydride)was given as a brown oily solid.

1H-NMR (CDCl₃) δ 3.55-3.35 (m, 2H), 2.4-2.2 (m, 2H), 2.15-1.75 (m, 5H),1.55-1.35 (m, 1H). ##STR275## Step 2--Preparation of Example 203.

Produced using the general method of Example 1 except that1,2-dichloroethane was used as solvent and the anhydride made in step 1was used instead of dihydro-3-(2-methylpropyl)-2,5-furandione. Theproduct (1.0 g, 43%) purified by chromatography on silica gel to yield aresidue containing both cis and trans isomers. The cis isomer Example203 (160 mg) was isolated by several recrystallizations.

MP 176°-178° C.; TLC (1/1 (v/v) EtOAc/hexane) Rf=0.37; ¹ H-NMR (CDCl₃) δ11.89 (bs, 1H), 8.02 (d, J=8.46 Hz, 2H), 7.81 (d, J=8.46 Hz, 2H), 7.77(d, J=8.82 Hz, 2H), 7.55 (d, J=8.46 Hz, 2H), 4.15-4.11 (m, 1H),3.14-3.11 (m, 1H), 2.03-1.61 (m, 6H); IR (nujol) 2983.4, 1708.7, 1679.7cm⁻¹ ; MS (FAB-LSIMS) 329 M+H!⁺ (C₁₉ H₁₇ ClO₃, FW=328.79); Anal. C:calcd, 69.40; found, 69.36. H: calcd, 5.21; found, 5.37. ##STR276##

EXAMPLE 204

To the trans isomer containing mother liquid of Example 203 (110 mg,0.334 mmol) in THF (5 mL), was added 1,8-Diazabicyclo 5.4.0! undec-7-ene(75 μL, 0.502 mmol) at room temperature. The reaction mixture wasstirred under argon for 48 hrs. Workup consisted of dilution with CH₂Cl₂ (15 mL), addition of 1N HCl (15 mL), separation, extraction of theaqueous with CH₂ Cl₂ (15 mL×3), drying the combined organic layers overMgSO₄, filtration and concentration in vacuo. The crude product (98 mg,89%) was purified by HPLC, to provide pure trans compound Example 204 asa white solid.

EXAMPLE 204

MP 169°-172° C.; TLC (1/1 (v/v) EtOAc/hexane) Rf=0.37; ¹ H-NMR (CDCl₃) δ8.05 (d, J=8.46, 2H), 7.63 (d, J=8.83 Hz, 2H), 7.53 (d, J=8.82 Hz, 2H),7.41 (d, J=8.83 Hz, 2H), 4.16-4.08 (m, 1H), 3.48-3.41 (m, 1H), 2.21-1.73(m, 6H); IR (nujol) 1700.9, 1672.0 cm⁻¹ ; MS (FAB-LSIMS) 329 M+H!⁺ (C₁₉H₁₇ ClO₃, FW=328.79); Anal. C: calcd, 69.40; found, 69.14. H: calcd,5.21; found, 5.13. ##STR277##

EXAMPLE 205 AND EXAMPLE 206

These compounds were produced using the general method of Example 1except that 1,2-dichloroethane was used as solvent andcyclobutanedicarboxylic anhydride was used instead ofdihydro-3-(2-methylpropyl)-2,5-furandione. The crude product (0.72 g,30%) contained a mixture ofcis and trans isomers (cis: trans=2/1):

MS (FAB-LSIMS) 315 M+H!⁺ (C₁₈ H₁₅ ClO₃, FW=314.84).

EXAMPLE 205

The crude product was purified by chromatography on silica gel toprovide 40 mg of the cis isomer as a white solid.

MP 154°-156° C.; TLC (1/10 (v/v) IPA/hexane) Rf=0.15; ¹ H-NMR (DMSO-d₆)δ 7.93 (d, J=8.46 Hz, 2H), 7.79 (d, J=7.72 Hz, 2H), 7.77 (d, J=8.46 Hz,2HO, 7.55 (d, J=8.83 Hz, 2H), 4.37-4.34 (m, 1H), 3.58-3.61 (m, 1H),2.42-2.04 (m, 4H); IR (nujol) 3079.8, 1699.0, 1681.7 cm⁻¹ ; MS (EI) 315M+H!⁺ (C₁₈ H₁₅ ClO₃, FW=314.84); Anal. C: calcd, 68.66; found, 68.27. H:calcd, 4.80; found, 4.43.

EXAMPLE 206

To the suspension of the crude two component product (14.5 g, 46.06mmol) in MeOH (250 mL) at room temperature, was added K₂ CO₃ (ex). Thereaction mixture was stirred at room temperature for 48 hrs. Workupconsisted of addition of 2N HCl (500 mL), extraction of the aqueouslayer with CH₂ Cl₂ (7×400 mL), washing the combined organic layers withsat. NaCl (1200 mL), drying over MgSO₄, filtration and concentration invacuo. The crude product (13.2 g, 91%) was given as off-white solid with84% de favor trans isomer. The recrystallization was carried out toprovide 9.1 g of pure trans material as white crystals.

MP 184°-186° C.; TLC (1/10 (v/v) IPA/hexane) Rf=0.15; ¹ H-NMR (DMSO-d₆)δ 12.3 (bs, 1H), 8.01 (d, J=8.45 Hz, 2H), 7.82 (d, J=8.46 Hz, 2H), 7.77(d, J=8.82 Hz, 2H), 7.55 (d, J=8.46 Hz, 2H), 4.35-4.27 (m, 1H),3.47-3.38 (m, 1H), 2.32-1.98 (m, 4H); ¹³ C-NMR (DMSO-d₆) δ 199.39,176.08, 144.46, 134.92, 134.47, 130.14, 129.91, 128.13, 44.75, 39.18,23.71, 22.37; IR (nujol) 3035.5, 1693.2, 1670.1 cm⁻¹ ; MS (EI) 315 M+H!⁺(C₁₈ H₁₅ ClO₃, FW=314.84); Anal. C: calcd, 68.66; found, 68.81. H:calcd, 4.80; found, 4.59.

EXAMPLE 207 ##STR278## Step 1--Preparation ofCyclopropane-1,2-dicarboxylic acid.

To the solution of 1,2-cis-dimethylcyclopropane dicarboxylate ester(4.71 g, 29.8 mmol) in THF (100 mL) at room temperature, was added 1NNaOH (150 mL). The reaction mixture was stirred under argon for 14 hrs.Workup consisted of separation of THF layer from the aqueous, washingthe aqueous with diethyl ether, acidification the aqueous with 2N HCl,concentration to dryness, dilution with EtOAc, filtration andconcentration in vacuo. The desired product (3.5 g, 90%) was given as awhite solid.

¹ H-NMR (DMSO-d₆) δ 4.21 (bs, 2H), 1.29-1.24 (m, 1H), 0.71-0.65 (m, 1H).##STR279## Step 2--Preparation of cis-Cyclopropane-1,2-dicarboxylicanhydride.

To the cyclopropane-1,2-dicarboxylic acid (3.24 g, 24.9 mmol) at roomtemperature, was added acetic anhydride (30 mL, ex). The reactionmixture was refluxed for 4 hrs. Workup consisted of concentration invacuo to provide the desired product.

¹ H-NMR (DMSO-d₆) δ 2.00 (dd, J=4.04, J'=8.08, 2H), 0.90-0.83 (m, 2H).##STR280## Step 3--Preparation of Example 207 (Reference with respect tocomposition).

Produced using the general method of Example 1 except that1,2-dichloroethane was used as solvent and the anhydride of step 2 abovewas used instead of dihydro-3-(2-methylpropyl)-2,5-furandione.

MP 175°-176° C.; ¹ H-NMR (DMSO-d₆) δ 12.16 (s, 1H), 8.08 (d, J=8.46 Hz,2H), 7.84 (d, J=8.45 Hz, 2H), 7.78 (d, J=8.46 Hz, 2H), 7.56 (d, J=8.46Hz, 2H), 3.05-2.97 (m, 1H), 2.33-2.25 (m, 1H), 1.57-1.51 (m, 1H),1.33-1.26 (m, 1H); ¹³ C-NMR (DMSO-d₆) δ 194.85, 144.25, 138.83, 136.98,134.42, 130.15, 129.91, 127.97, 27.33, 23.76, 12.07; IR (nujol) 1689.4,1673.9, 1604.5 cm⁻¹ ; MS (FAB-LSIMS) 301 M+H!⁺ (C₁₇ H₁₃ ClO₃, FW=300.7);Anal. C: calcd, 67.89; found, 68.06. H: calcd, 4.36; found, 4.15.##STR281##

EXAMPLE 208 (Reference with respect to composition)

To the solution of Example 207 (50 mg, 0.166 mmol) in MeOH (20 mL) atroom temperature, was added K₂ CO₃ (ex). The reaction mixture wasstirred at room temperature for 48 hrs. Workup consisted of addition of1N HCl (25 mL), extraction of the aqueous layer with CH₂ Cl₂ (4×25 mL),washing the combined organic layers with sat. NaCl (50 mL), drying overMgSO₄, filtration and concentration in vacuo. The product (50 mg, 100%)was given as a white solid with >99% de favor trans isomer.

MP 181°-183° C.; ¹ H-NMR (DMSO-d₆) δ 12.65 (s, 1H), 8.13 (d, J=8.46 Hz,2H), 7.86 (d, J=8.46 Hz, 2H), 7.79 (d, J=8.46 Hz, 2H), 7.56 (d, J=8.45Hz, 2H), 3.28-3.22 (m, 1H), 2.14-2.08 (m, 1H), 1.52-1.45 (m, 2H); MS(FAB-LSIMS) 301 M+H!⁺ (C₁₇ H₁₃ ClO₃, FW=300.7); Anal. C: calcd, 67.89;found, 67.95. H: calcd, 4.36; found, 4.34.

EXAMPLE 209 AND EXAMPLE 210 ##STR282## Step 1

Using the general method of Example 1 except that the solvent was1,2-dichloroethane and 1-Cyclopentene-1,2-dicarboxylic anhydride wasused instead of dihydro-3-(2-methylpropyl)-2,5-furandione, the abovecompound (27.7 g) was obtained as white crystals in 91% yield.

MP 226°-227° C.; ¹ H NMR (DMSO-d₆) δ 7.90 (d, J=8.46 Hz, 2H), 7.62 (d,J=8.46 Hz, 2H), 7.54 (d, J=8.83 Hz, 2H), 7.44 (d, J=8.82 Hz, 2H),2.89-2.78 (m, 2H), 2.16-2.06 (m, 2H); ¹³ C NMR (DMSO-d₆) δ 196.77,166.07, 153.31, 144.77, 138.81, 135.60, 135.43, 134.53, 130.36, 130.20,129.96, 128.25, 38.23, 33.97, 23.35. ##STR283## Step 2

To the solution of diisopropylamine (19 mL, 130 mmol) in THF (60 mL) at-78° C., was added n-Butyl lithium (78 mL, 125 mmol). The formed LDA wasstirred for 30 min at -78° C. and then treated with a solution of theproduct from step 1 (10.2 g, 31.2 mmol) in THF (100 ML). The reactionmixture was stirred under argon at -78° C. for 1.5 hrs, and quenchedwith AcOH (21 mL, 375 mmol). The resulting mixture was allowed to warmto room temperature during a period of 2 hrs. Workup consisted ofaddition of 1N HCl (100 mL), extraction of the aqueous with CH₂ Cl₂(3×150 mL), and concentration in vacuo. The crude product wasrecrystallized from EtOAc to provide 6.22 g of the above compound asoff-white crystals.

MP 202°-204° C.; ¹ H NMR (DMSO-d₆) δ 8.06 (d, J=8.46 Hz, 2H), 7.64 (d,J=8.09 Hz, 2H), 7.54 (d, J=8.46 Hz, 2H), 7.43 (d, J=8.45 Hz, 2H), 7.14(m, 1H), 4.80-4.75 (m, 1H), 2.75-2.44 (m, 3H), 2.11-2.00 (m, 1H); ¹³ CNMR (DMSO-d₆) δ 201.25, 166.39, 146.46, 144.35, 138.81, 137.79, 136.11,134.47, 130.36, 130.18, 129.94, 128.10, 52.20, 33.50, 29.83. ##STR284##Step 3--Preparation of Example 209 and Example 210.

To a solution of the product from step 2 (919 mg, 2.81 mmol) in DMF (6mL) at room temperature under argon, was added thiophenol (433 μL, 4.22mmol) and K₂ CO₃ in H₂ O (2M, 141 μL, 0.281 mmol). The reaction mixturewas stirred under argon at room temperature for 18 hrs. Workup consistedof dilution with CH₂ Cl₂ (15 mL), acidification with 2N HCl, addition ofH₂ O (20 mL), washing the organic layer with H₂ O (3×40 mL), sat. NaCl(30 mL), drying over MgSO₄, filtration and concentration in vacuo. Thecrude product was purified by chromatography on silica gel to providetwo separated diastereomers, trans-trans Example 209 and trans-cisExample 210 in a total yield of 46%.

EXAMPLE 209

MP 177°-178° C.; ¹ H NMR (CDCl₃) δ 8.01 (d, J=8.46 Hz, 2H), 7.64 (d,J=8.82 Hz, 2H), 7.54 (d, J=8.83 Hz, 2H), 7.47-7.41 (m, 4H), 7.30-7.25(m, 3H), 4.13-4.08 (m, 1H), 3.91-3.88 (m, 1H), 3.60-3.55 (m, 1H),2.28-2.19 (m, 2H), 2.01-1.83 (m, 2H); IR (nujol) 3075.9, 1710.6, 1675.9cm⁻¹ ; MS (FAB-LSIMS) 337 M+H!⁺ (C₂₅ H₂₁ ClO₃ S, FW=436.94); Anal. C:calcd, 68.72; found, 68.61. H: calcd, 4.85; found, 4.76.

EXAMPLE 210

MP 184°-185° C.; ¹ H NMR (CDCl₃) δ 8.07 (d, J=8.45 Hz, 2H), 7.66 (d,J=8.45 Hz, 2H), 7.56 (d, J=8.86 Hz, 2H), 7.47-7.43 (m, 4H), 7.29-7.25(m, 3H), 4.43-4.34 (m, 1H), 4.11-4.05 (m, 1H), 3.95-3.90 (m, 1H),2.57-2.49 (m, 1H), 2.22-2.13 (m, 1H), 2.11-2.02 (m, 1H), 1.83-1.73 (m,1H); IR (nujol) 3074.0, 1708.6, 1673.9, 1604.5 cm⁻¹ ; MS (FAB-LSIMS) 337M+H!⁺ (C₂₅ H₂₁ ClO₃ S, FW=436.94); Anal. C: calcd, 68.72; found, 68.52.H: calcd, 4.85; found, 4.81.

EXAMPLE 211 AND EXAMPLE 212

Enantiomeric separation of Example 209 was carried out by using aDiacel® AD semi-prep column (2 cm×25 cm) with 15% IPA (with 1% H₂ O and0.1% TFA) in hexane to provide enantiomer Example 211 with >98% ee, andenantiomer Example 212 with >97% ee.

EXAMPLE 211

(+)-enantiomer; MP 165°-167° C.; Anal. C: calcd, 68.72; found, 68.59. H:calcd, 4.85; found, 4.64.

EXAMPLE 212

(-)-enantiomer; MP 168°-169° C.; Anal. C: calcd, 68.72; found, 68.39. H:calcd, 4.85; found, 4.67.

EXAMPLE 213, EXAMPLE 214, EXAMPLE 215, EXAMPLE 216, EXAMPLE 217, EXAMPLE218, EXAMPLE 219, EXAMPLE 220, EXAMPLE 221, EXAMPLE 222, AND EXAMPLE 223

Example 213, Example 214, Example 215, Example 216, Example 217, Example218, Example 219, Example 220, Example 221, Example 222 and Example 223were made in a similar method to that used for Example 209 except thatthe indicated thiol-containing compounds were used instead ofthiophenol. ##STR285##

EXAMPLE 213

From 4-florothiophenol: MP 164°-166° C.; ¹ H NMR (CDCl₃) δ 7.90 (m, 2H),7.52 (m, 2H), 7.43 (m, 2H), 7.39-7.29 (m, 4H), 6.88 (m, 2H), 4.03 (m,1H), 3.74 (m, 1H), 3.32 (m, 1H), 2.05 (m, 2H), 1.84 (m, 1H), 1.67 (m,1H); MS (FAB-LSIMS) 455 M+H!⁺ (C₂₅ H₂₀ ClFO₃ S, FW=454.95); Anal. C:calcd, 66.00; found, 65.90. H: calcd, 4.43; found, 4.51. ##STR286##

EXAMPLE 214

From 4-florothiophenol: ¹ H NMR (CDCl₃) δ 7.98 (d, J=8.46 Hz, 2H), 7.60(d, J=8.45 Hz, 2H), 7.54 (d, J=8.46 Hz, 2H), 7.44 (d, J=8.82 Hz,2H),7.30-7.29 (m, 2H), 6.88 (m, 2H), 4.23 (m, 1H), 3.79 (m, 1H), 3.46(m, 1H), 2.32-2.08 (m, 3H), 1.86 (m, 1H); MS (FAB-LSIMS) 455 M+H!⁺ (C₂₅H₂₀ ClFO₃ S, FW=454.95). ##STR287##

EXAMPLE 215

From 4-florothiophenol: MP 211°-212° C.; ¹ H NMR (CDCl₃) δ 7.89 (d,J=8.09 Hz, 2H), 7.49 (d, J=8.45 Hz, 2H), 7.40 (d, J=8.45 Hz, 2H),7.30-7.25 (m, 2H), 6.84 (m, 2H), 4.19 (m, 1H), 3.78 (m, 1H), 3.62 (m,1H), 2.32 (m, 1H), 1.97-1.78 (m, 2H), 1.58 (m, 1H); MS (FAB-LSIMS) 455M+H!⁺ (C₂₅ H₂₀ ClFO₃ S, FW=454.95); Anal. C: calcd, 66.00; found, 65.98.H: calcd, 4.43; found, 4.48. ##STR288##

EXAMPLE 216

From o-thiocresol: MP 175°-176° C.; ¹ H NMR (CDCl₃) δ 8.02 (d, J=8.46Hz, 2H), 7.64 (d, J=8.83 Hz, 2H), 7.54 (d, J=8.82 Hz, 2H), 7.43 (d,J=8.46 Hz, 2H), 7.47-7.41 (m, 1H), 7.14-7.13 (m, 3H), 4.12 (m, 1H), 3.91(m, 1H), 3.62 (m, 1H), 2.24 (m, 2H), 2.02 (m, 1H), 1.85 (m, 1H); IR(nujol) 3074.0, 1708.6, 1673.9, 1604.5 cm⁻¹ ; MS (FAB-LSIMS) 451 M+H!⁺(C₂₆ H₂₃ ClO₃ S, FW=450.99); Anal. C: calcd, 69.24; found, 69.20. H:calcd, 5.14; found, 5.07. ##STR289##

EXAMPLE 217

From o-thiocresol: ¹ H NMR (CDCl₃) δ 8.01 (d, J=8.46 Hz, 2H), 7.59 (d,J=8.83 Hz, 2H), 7.54 (d, J=8.45 Hz, 2H), 7.43 (d, J=8.82 Hz, 2H),7.29(m, 1H), 7.12-7.02 (m, 3H), 4.26 (m, 1H), 3.82 (m, 1H), 3.55 (m,1H), 2.37-2.07 (m, 3H), 1.94-1.83 (m, 1H); MS (FAB-LSIMS) 451 M+H!⁺ (C₂₆H₂₃ ClO₃ S, FW=450.99). ##STR290##

EXAMPLE 218

From o-thiocresol: MP 196°-197° C.; ¹ H NMR (CDCl₃) δ 8.09 (d, J=8.46Hz, 2H), 7.67 (d, J=8.45 Hz, 2H), 7.56 (d, J=8.83 Hz, 2H), 7.44 (d,J=8.83 Hz, 2H), 7.45 (m, 1H), 7.16 (m, 3H), 4.12 (m, 1H), 4.06 (m, 1H),3.96 (m, 1H), 2.58 (m, 1H), 2.14 (m, 1H), 2.05 (m, 1H), 1.81 (m, 1H); MS(FAB-LSIMS) 451 M+H!⁺ (C₂₆ H₂₃ ClO₃ S, FW=450.99); Anal. C: calcd,69.24; found, 69.27. H: calcd, 5.14; found, 5.20. ##STR291##

EXAMPLE 219

From o-methylthiosalicylate: ¹ H NMR (CDCl₃) δ 8.03 (d, J=8.83 Hz, 2H),7.90 (m, 1H), 7.64 (d, J=8.82 Hz, 2H), 7.54 (d, J=8.82 Hz, 2H),7.46-7.42 (m, 4H), 7.19 (m, 1H), 4.17-4.04 (m, 2H), 3.70 (m, 1H),2.64-2.24 (m, 2H), 2.10-1.90 (m, 2H); MS (FAB-LSIMS) 495 M+H!⁺ (C₂₇ H₂₃ClO₅ S, FW=494.99). ##STR292##

EXAMPLE 220

From o-methylthiosalicylate: ¹ H NMR (CDCl₃) δ 8.10 (d, J=8.82 Hz, 2H),7.86 (m, 1H), 7.60 (d, J=8.83 Hz, 2H), 7.52 (d, J=8.82 Hz, 2H), 7.41 (d,J=9.83 Hz, 2H), 7.28 (m, 2H), 7.11 (m, 1H), 4.30 (m, 1H), 4.03 (m, 1H),3.50 (m,1H), 2.37-2.23 (m, 3H), 2.00-1.93 (m, 1H); MS (FAB-LSIMS) 495M+H!⁺ (C₂₇ H₂₃ ClO₅ S, FW=494.99). ##STR293##

EXAMPLE 221

From o-methylthiosalicylate: MP 227°-228° C.; ¹ H NMR (CDCl₃) δ 7.90 (m,2H), 7.72 (m, 1H), 7.50 (m, 2H), 7.40 (m, 2H), 7.35-7.25 (m, 4H), 7.02(m, 1H), 4.26 (m, 1H), 3.90 (m, 1H), 3.76 (m, 1H), 2.35 (m, 1H), 2.08(m, 1H), 1.94 (m, 1H), 1.62 (m,1H); MS (FAB-LSIMS) 495 M+H!⁺ (C₂₇ H₂₃ClO₅ S, FW=494.99); Anal. C: calcd, 65.51; found, 65.17. H: calcd, 4.68;found, 4.73. ##STR294##

EXAMPLE 222

From 4-chlorothiophenol: MP 213°-214° C.; ¹ H NMR (CDCl₃) δ 7.99 (d,J=8.46 Hz, 2H), 7.60 (d, J=8.46 Hz, 2H), 7.51 (d, J=8.82 Hz, 2H), 7.40(d, J=8.46 Hz, 2H), 7.37 (d, J=8.09 Hz, 2H), 7.22 (d, J=8.46 Hz, 2H),4.12 (m, 1H), 3.91 (m, 1H), 3.44 (m, 1H), 2.17 (m, 2H), 1.94 (m, 1H),1.78 (m, 1H); MS (FAB-LSIMS) 471 M+H!⁺ (C₂₅ H₂₀ Cl₂ O₃ S, FW=470); Anal.C: calcd, 63.69; found, 63.68. H: calcd, 4.28; found, 4.28. ##STR295##

EXAMPLE 223

From 4-chlorothiophenol: MP 210°-211° C.; ¹ H NMR (CDCl₃) δ 8.06 (d,J=8.46 Hz, 2H), 7.67 (d, J=8.09 Hz, 2H), 7.56 (d, J=8.83 Hz, 2H), 7.44(d, J=8.46 Hz, 2H), 7.39 (d, J=8.46 Hz, 2H), 7.28 (m, 2H), 4.37 (m, 1H),4.04 (m, 1H), 3.94 (m, 1H), 2.52 (m, 1H), 2.19 (m, 1H), 2.05 (m, 1H),1.81 (m, 1H); MS (FAB-LSIMS) 471 M+H!⁺ (C₂₅ H₂₀ Cl₂ O₃ S, FW=470); Anal.C: calcd, 63.69; found, 63.58. H: calcd, 4.28; found, 4.31.

EXAMPLE 224 AND EXAMPLE 225 ##STR296## Step 1--Preparation of Ethyl4-(4-bromophenyl) phenyl ether.

To a solution of 4-(4-bromophenyl)-phenol (4.06 g, 16.3 mmol) in acetone(30 mL) at room temperature, was added 4.5 eq K₂ CO₃ (4.0M, 18 mL, 73.3mmol) in water and 4.0 eq lodoethane (5.26 mL, 65.2 mmol). The reactionmixture was stirred overnight, and heated to reflux for 6 hrs. Theproduct was crystallized out of the solution, and filtered. The crudeproduct was recrystallized from hexane to provide ethyl4-(4-bromophenyl) phenyl ether (4.1 g, 91%) as an white crystal.

¹ H NMR (CDCl₃) δ 7.53 (d, J=8.83 Hz, 2H), 7.47 (d, J=6.62 Hz, 2H), 7.41(d, J=8.46 Hz, 2H), 6.96 (d, J=8.82 Hz, 2H), 4.07 (q, J=6.99 Hz, 2H),1.44 (t, J=6.99 Hz, 3H). ##STR297## Step 2

To the solution of ethyl 4-(4-bromophenyl) phenyl ether (12.87 g, 46.43mmol) in THF (90 mL), was added t-BuLi (1.7M, 54.6 mL, 92.87 mmol) at-78° C. The reaction mixture was stirred under argon at -78° C. for 3hrs, and treated with 1-cyclopentene-1,2-dicarboxylic anhydride (6.73 g,48.75 mmol). The resulting mixture was stirred at -78° C. for 2 hrs, andthen warmed to room temperature. Workup consisted of addition of 1N HCl(150 mL), extraction with EtOAc (4×200 mL), and concentration in vacuo.The crude product (18 g) was recrystallized from EtOAc to provide theintermediate acylacrylic acid (6.8 g, 43%) as an off-white solid.

¹ H NMR (CDCl₃) δ 7.88 (d, J=8.09 Hz, 2H), 7.63 (d, J=8.45 Hz, 2H), 7.56(d, J=8.82 Hz, 2H), 6.98 (d, J=9.19 Hz, 2H), 4.09 (q, J=6.99 Hz, 2H),2.84 (m, 4H), 2.10 (m, 2H), 1.45 (t, J=6.99 Hz, 3H). ##STR298## Step 3

To the solution of intermediate from step 2 (3.45 g, 10.25 mmol) in THF(100 mL) at -78° C., was added 4.0 eq LiN(TMS)₂ (1M, 41.03 mL, 41.03mmol). The resulting yellow mixture was stirred under argon at -78° C.for 18 hrs, quenched with AcOH (˜10 mL), and then allowed to warm toroom temperature. Workup consisted of addition of 1N HCl (120 mL),extraction with EtOAc (4×130 mL), washing the combined organic layerswith sat. NaCl (250 mL), drying over MgSO₄, filtration and concentrationin vacuo. The crude product was purified by recrystallization from EtOActo provide a rearranged acrylic acid intermediate (2.40 g, 70%) as anoff-white solid.

¹ H NMR (CDCl₃) δ 7.89 (d, J=8.64 Hz, 2H), 7.50 (d, J=8.09 Hz, 2H), 7.42(d, J=8.83 Hz, 2H), 6.85 (s, 1H), 6.83 (d, J=8.83 Hz, 2H), 4.64 (m, 1H),3.94 (q, J=6.99 Hz, 2H), 2.47 (m, 2H), 2.35 (m, 1H), 1.85 (m, 1H), 1.29(t, J=6.99 Hz, 3H). ##STR299## Step 4--Preparation of Example 224 andExample 225.

To the solution of intermediate from step 3 (510 mg, 1.52 mmol) in DMF(2 mL) at room temperature under argon, was added thiophenol (311 μL,3.03 mmol) and freshly made K₂ CO₃ in H₂ O (2M, 75 μL, 0.15 mmol). Thehomogeneous solution was stirred at room temperature overnight. Workupconsisted of acidification with 2N HCl (1 mL), addition of H₂ O (10 mL),extraction with CH₂ Cl₂ (2×15 mL), filtration through silica, andconcentration in vacuo. The crude product was purified by HPLC (0-8%EtOAc/CH₂ Cl₂) to provide two separated diastereomers, trans-transisomer Example 224 and trans-cis isomer Example 225.

EXAMPLE 224

¹ H NMR (CDCl₃) δ 7.99 (d, J=8.82 Hz, 2H), 7.63 (d, J=8.46 Hz, 2H), 7.55(d, J=8.83 Hz, 2H), 7.48 (m, 2H), 7.29-7.20 (m, 3H), 6.98 (d, J=9.19 Hz,2H), 4.10 (m, 1H), 4.08 (q, J=6.99 Hz, 2H), 3.90 (m, 1H), 3.58 (m, 1H),2.35 (m, 2H), 1.95 (m, 1H), 1.85 (m, 1H), 1.44 (t, J=6.99 Hz, 3H); MS(FAB-LSIMS) 447 M+H!⁺ (C₂₇ H₂₆ O₄ S, FW=446.54); Anal. C: calcd, 72.62;found, 72.74; H: calcd, 5.87; found, 5.84.

EXAMPLE 225

¹ H NMR (CDCl₃) δ 8.03 (d, J=8.45 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.55(d, J=8.46 Hz, 2H), 7.44 (m, 2H), 7.29-7.15 (m, 3H), 6.97 (d, J=8.82 Hz,2H), 4.36 (m, 1H), 4.07 (q, J=6.99 Hz, 2H), 4.07 (m, 1H), 3.90 (m, 1H),2.50 (m, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.75 (m, 1H), 1.43 (t, J=6.99Hz, 3H); MS (FAB-LSIMS) 447 M+H!⁺ (C₂₇ H₂₆ O₄ S, FW=446.54); Anal. C:calcd, 72.62; found, 72.39; H: calcd, 5.87; found, 5.87.

EXAMPLE 226 ##STR300## Step 1

To the solution of diisopropylamine (30.8 mL, 220 mmol) in THF (100 mL)at -78° C., was added n-BuLi (2M, 100 mL, 200 mmol). The LDA solutionwas stirred at -78° C. for 30 min., and followed by addition ofethyl-2-oxocyclopentanecarboxylate (15.6 g, 14.8 mL, 100 mmol). Thereaction mixture was allowed to warm to 0° C. for 30 min. After coolingdown to -78° C., the reaction mixture was treated with benzyl chloride(12.66 g, 11.51 mL, 100 mmol). The resulting mixture was warmed to 0° C.for 3 hrs. Workup consisted of acidification with 2N HCl (100 mL),extraction with EtOAc (4×100 mL), drying over MgSO₄, filtration andconcentration in vacuo. The crude product was purified by MPLC (5-15%EtOAc/hexane) to provide the indicated intermediate (7.1 g, 29%) as aclear oil. ##STR301## Step 2

To the solution of intermediate from step 1 (7.28 g, 29.56 mmol) in EtOH(50 mL) at 0° C., was added NaBH₄ (1.12 g, 29.56 mmol). The reactionmixture was stirred at room temperature for 3 hrs under argon, and thenquenched by sat. NH₄ Cl (100 mL). Workup consisted of extraction withEtOAc (4×100 mL), drying over MgSO₄, filtration and concentration invacuo. The crude product was given as an yellow oil. ##STR302## Step 3

To the solution of triphenylphosphine (14.64 g, 55.8 mmol) and DEAD(7.99 mL, 50.74 mmol) in THF (100 mL) at room temperature, was added thesolution of intermediate from step 2 (6.30 g, 25.37 mmol) in THF (˜50mL). The reaction mixture was refluxed overnight under argon. Workupconsisted of concentration in vacuo. The crude product was purified byMPLC twice (2% EtOAc/hexane) to provide the above intermediate (2.85 g,49%).

¹ H NMR (CDCl₃) δ 7.35-7.15 (m, 5H), 6.68 (bs, 1H), 4.20 (q, 2H), 3.15(m, 1H), 2.80-2.45 (m, 4H), 2.10 (m, 1H), 1.65 (m, 1H), 1.29 (t, 3H).##STR303## Step 4

To the solution of intermediate from step 3 (2.8 g, 12.16 mmol) in DME(35 mL) at room temperature, was added LiOH.H₂ O (5.1 g, 121.6 mmol) inH₂ O (˜35 mL). The resulting mixture was heated to reflux for 3 hrs.Workup consisted of acidification with 2N HCl (˜100 mL), extraction withEtOAc (4×100 mL), washing the combined organic layers with sat. NaCl,drying over MgSO₄, filtration, concentration and co-evaporation withtoluene (3×50 mL). The desired intermediate as shown above (2.35 g, 96%)was given as a white solid.

¹ H NMR (CDCl₃) δ 7.35-7.15 (m, 5H), 3.15 (m, 1H), 2.80-2.65 (m, 2H),2.65-2.45 (m, 2H), 2.15 (m, 1H), 1.70 (m, 1H). ##STR304## Step 5

To the solution of intermediate from step 4 (2.3 g, 11.34 mmol) in THF(80 mL) at 0° C., was added DCC (2.82 g, 13.65 mmol), and HOBT (1.84 g,13.65 mmol). The resulting mixture was stirred for about 1 hr, andfollowed by addition of N,O-dimethyl-hydroxylamine hydrochloride (2.22g, 22.74 mmol) and Et₃ N (3.96 mL, 28.43 mmol). The reaction mixture wasallowed to warm to room temperature and stirred overnight. Workupconsisted of filtration, washing the filter cake with EtOAc,concentration in vacuo. The crude product was purified by HPLC (elution:7-15% EtOAc/CH₂ Cl₂) to provide intermediate as shown above (2.56 g,92%) as light yellow oil.

¹ H NMR (CDCl₃) δ 7.25 (m, 2H), 7.15 (m, 3H), 6.38 (m, 1H), 3.55 (s,3H), 3.20 (s, 3H), 3.10 (m, 1H), 2.65 (m, 4H), 2.05 (m, 1H), 1.60 (m,1H). ##STR305## Step 6

To the solution of ethyl 4-(4-bromophenyl) phenyl ether (830 mg, 2.99mmol) in THF (6 mL), was added t-BuLi (1.7M, 3.52 mL, 5.99 mmol) at -78°C. The reaction mixture was stirred under argon at -78° C. for 1 hrs,and treated with intermediate from step 5 (770 mg, 3.14 mmol). Theresulting mixture was stirred at -78° C. for 30 min., 0° C. for 30 min.,and room temperature for 30 min. Workup consisted of addition of 1N HCl(25 mL), extraction with EtOAc (4×20 mL), filtration through silica, andconcentration in vacuo. The crude product was purified by HPLC (elution:5-20% EtOAc/hexane) to provide the intermediate as shown above (400 mg,35%) as an off-white solid.

¹ H NMR (CDCl₃) δ 7.80 (d, J=8.46 Hz, 2H), 7.62 (d, J=8.46 Hz, 2H), 7.57(d, J=8.83 Hz, 2H), 7.29 (m, 2H), 7.21 (m, 3H), 7.00 (d, J=8.82, 2H),6.46 (bs, 1H), 4.10 (q, J=6.99 Hz, 2H), 3.30 (m, 1H), 2.84 (m, 4H), 2.20(m, 1H), 1.75 (m, 1H), 1.46 (t, J=6.99 Hz, 3H). ##STR306## Step 7

To the solution of intermediate from step 6 (205 mg, 0.53 mmol) intoluene (5 mL) at 0° C., was added diethylaluminum cyanide (1N, 2.1 mL,2.1 mmol) in toluene. The reaction mixture was stirred at roomtemperature for 2 hrs under argon. Workup consisted of addition of 1NHCl (20 mL), extraction with EtOAc (4×20 mL), washing the combinedorganic layers with sat. NaCl, drying over MgSO₄, filtration andconcentration in vacuo. The crude product was carried to the next step.##STR307## Step 8

To the solution of the crude intermediate from step 7 in dioxane (5 mL)at room temperature, was added 50% H₂ SO₄ (5 mL). The reaction mixturewas refluxed for 18 hrs. Workup consisted of addition of EtOAc (25 mL),washing the organic layer with H₂ O (3×15 mL), drying over MgSO₄,filtration and concentration in vacuo. The crude product was carried tothe next step. ##STR308## Step 9--Preparation of Example 226.

To the solution of crude intermediate from step 8 in THF (5 mL) at roomtemperature, was added DBU (ex). The reaction mixture was stirredovernight. Workup consisted of dilution with EtOAc (30 mL), washing with2N HCl (2×10 mL), filtration through silica and concentration in vacuo.The crude product was purified by HPLC and recrystallization from EtOActo provide Example 226 as off-white solid.

MP: 138°-139° C.; ¹ H NMR (DMSO-d6) δ 8.02 (d, J=8.45 Hz, 2H), 7.77 (d,J=8.82 Hz, 2H), 7.69 (d, J=8.83 Hz, 2H), 7.27 (m, 2H), 7.20 (m, 3H),7.03 (d, J=8.82 Hz, 2H), 4.15 (m, 1H), 4.06 (q, J=6.99 Hz, 2H), 2.95 (m,2H), 2.55 (m, 1H), 2.45 (m, 1H), 2.10 (m, 1H), 1.70 (m, 2H), 1.35 (m,1H), 1.32 (t, J=6.99 Hz, 3H). MS (FAB-LSIMS) 429 M+H!⁺ (C₂₈ H₂₈ O₄,FW=428.50); Anal. C: calcd, 78.48; found, 78.21; H: calcd, 6.59; found,6.38. ##STR309##

EXAMPLE 227

Example 227 was obtained through the same synthetic sequence preparingExample 226, by using 4-bromo-4'-chloro biphenyl in the place of ethyl4-(4-bromophenyl) phenyl ether at step 6.

MP: 170°-171° C.; ¹ H NMR (DMSO-d6) δ 12.35 (s, 1H), 8.06 (d, J=8.46 Hz,2H), 7.83 (d, J=8.46 Hz, 2H), 7.78 (d, J=8.46 Hz, 2H), 7.55 (d, J=8.83Hz, 2H), 7.26 (m, 2H), 7.19 (m, 3H), 4.15 (m, 1H), 2.97 (m, 2H), 2.55(m, 1H), 2.45 (m, 1H), 2.10 (m, 1H), 1.70 (m, 2H), 1.40 (m, 1H). MS(FAB-LSIMS) 419 M+H!⁺ (C₂₆ H₂₃ ClO₃, FW=418.89); Anal. C: calcd, 74.54;found, 74.27; H: calcd, 5.53; found, 5.35. ##STR310##

EXAMPLE 228

To the suspension of 4-Oxo-4-(4'-chloro-4-biphenyl)but-2-enoic acid,Example 34 (0.941 g, 3.28 mmol) in MeOH (5 mL) at room temperature, wasadded 2,3-dimethyl-1,3-butadiene (2.69 g, 3.71 mL, 32.8 mmol). Thereaction mixture was refluxed under argon for a total of 2.5 hours.Workup consisted of concentration in vacuo. The crude product waspurified by recrystallization from MeOH to yield 950 mg Example 228 as awhite solid.

MP 217.0°-220.0° C.; TLC (1/1 (v/v) EtOAc/hexane) Rf=0.23; ¹ H NMR(DMSO-d6) δ 12.22 (s, 1H), 8.07 (d, J=8.45 Hz, 2H), 7.81 (d, J=8.09 Hz,2H), 7.76 (d, J=8.46, 2H), 7.54 (d, J=8.46, 2H), 3.79 (m, 1H), 2.81 (m,1H), 2.23 (m, 3H), 1.87 (m, 1H), 1.62 (s, 3H), 1.56 (s, 3H); IR (nujol)1706.7, 1673.9, 1604.5 cm⁻¹ ; MS (FAB-LSIMS) 369 M+H!⁺ (C₂₂ H₂₁ ClO₃,FW=368.91); Anal. C: calcd, 71.62; found, 71.49. H: calcd, 5.74; found,5.50. ##STR311##

EXAMPLE 229

To the suspension of 4-Oxo-4-(4'-chloro-4-biphenyl)but-2-enoic acid,Example 34 (1.01 g, 3.53 mmol) in MeOH (5 mL) at -78° C., was addedbutadiene (ex) for 30 min, and followed by addition of DMF (5 mL). Thereaction mixture was refluxed under argon for a total of 72 hours.Workup consisted of dilution with EtOAc (15 mL), addition of water (15mL), and extraction of the aqueous layer with EtOAc(3×15 mL). Thecombined organic layers were washed with sat. NaCl, dried over MgSO₄,and concentrated in vacuo. The crude product was purified bychromatography (EtOAc/hexane) to yield 140 mg Example 229 as a whitesolid.

MP 185.0°-186.0° C.; TLC (1/1 (v/v) EtOAc/hexane) Rf=0.23; ¹ H NMR(CDCl₃) δ 8.05 (d, J=8.46 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.55 (d,J=8.82, 2H), 7.44 (d, J=8.82, 2H), 5.76 (m, 2H), 3.82 (m, 1H), 3.14 (m,1H), 2.6-1.9 (m, 4H); IR (nujol) 1702.9, 1677.8, 1604.5 cm⁻¹ ; MS(FAB-LSIMS) 341 M+H!⁺ (C₂₀ H₁₇ ClO₃, FW=340.85); Anal. C: calcd, 70.47;found, 70.38. H: calcd, 5.03; found, 4.93. ##STR312##

EXAMPLE 230

To the suspension of 4-Oxo-4-(4'-chloro-4-biphenyl)but-2-enoic acid,Example 34 (1.208 g, 4.21 mmol) in MeOH (5 mL) at room temperature, wasadded isoprene (2.87 g, 4.21 mL, 42.1 mmol). The reaction mixture wasrefluxed under argon overnight. Workup consisted of concentration invacuo. The crude product was purified by chromatography (EtOAc/hexane)and recrystallization (three times) to yield 20 mg Example 230 as awhite solid.

MP 174.0°-177.0° C.; TLC (1/1 (v/v) EtOAc/hexane) Rf=0.20; ¹ H NMR(CDCl₃) δ 8.05 (d, J=6.99 Hz, 2H), 7.66 (d, J=8.09 Hz, 2H), 7.57 (d,J=8.46 Hz, 2H), 7.46 (d, J=8.46 Hz, 2H), 5.44 (m,1H), 3.78 (m, 1H), 3.20(m, 1H), 2.5-2.0 (m, 4H), 1.75 (s, 1H); IR (nujol) 1702.9, 1675.9,1604.5 cm⁻¹ ; MS (FAB-LSIMS) 355 M+H!⁺ (C₂₁ H₁₉ ClO₃, FW=354.8); Anal.C: calcd, 71.07; found, 70.85. H: calcd, 5.40; found, 5.62. ##STR313##

EXAMPLE 231

To the solution of 4-Oxo-4-(4'-chloro-4-biphenyl)but-2-enoic acid,Example 34 (1.123 g, 3.915 mmol) in THF (7 mL) at room temperature, wasadded 5 eq. 1,3-cyclohexadiene (1.87 mL, 19.577 mmol). The reactionmixture was stirred under refluxed for 18 hrs. Workup consisted ofconcentration in vacuo. The crude product was purified by HPLC toprovide the desired product Example 231 (570 mg, 40%) as a white solidcontaining two isomers.

MP 174°-176° C.; TLC (1/20 (v/v) MeOH/CH₂ Cl₂) Rf=0.27; ¹ H NMR(DMSO-d6) consistent with structure; IR (nujol) 1704.8, 1677.8, 1602.6cm⁻¹ ; MS (FAB-LSIMS) 367 M+H!⁺ (C₂₂ H₁₉ ClO₃, FW=366.88); Anal. C:calcd, 72.03; found, 72.03. H: calcd, 5.22; found, 5.08. ##STR314##

EXAMPLE 232

The mixture of Example 231 (299 mg, 0.815 mmol) and p-Toluene-sulfonohydrazide (1.5 g, 8.15 mmol) was dissolved in dimethoxyethane (20 mL),and allowed to warm to reflux. The solution of Sodium acetate (1.0 g,12.2 mmol) in water (16 mL) was added over a period of 4 hrs. Thereaction mixture was cooled to room temperature, poured into water (120mL), and extracted with CH₂ Cl₂ (4×70 mL). The combined organic layerswere washed with 150 mL water, dried over MgSO₄ and concentrated invacuo. The crude product was purified by HPLC to provide the desiredproduct Example 232 (85 mg, 28%).

MP 191°-193° C.; ¹ H NMR (DMSO-d6) δ 12.33 (s, 1H), 8.07 (d, J=8.45 Hz,2H), 7.83 (d, J=8.09 Hz, 2H), 7.77 (d, J=8.46 Hz, 2H), 7.56 (d, J=8.46Hz, 2H), 4.00 (d, J=7.35 Hz, 1H), 3.22 (d, J=7.35 Hz, 1H), 2.10 (bs,1H), 1.87 (bs, 2H), 1.55-1.45 (m, 5H), 1.26-1.23 (m, 2H); IR (nujol)1704.8, 1664.3, 1604.5 cm⁻¹ ; MS (FAB-LSIMS) 369 M+H!⁺ (C₂₂ H₂₁ ClO₃,FW=368.89); Anal. C: calcd, 71.63; found, 71.92. H: calcd, 5.74; found,5.67. ##STR315##

EXAMPLE 233 (Reference with respect to composition)

This compound was prepared by a similar method to that used for Example30, except that the indicated anhydride was used instead of itaconicanhydride. From glutaric anhydride:

MP: 174°-176° C.; TLC (methylene chloride--5% methanol) R_(f) 0.183; ¹ HNMR (CDCl₃) δ 8.05 (d, J=8.8 Hz, 2 H), 7.66 (d, J=8.07 Hz, 2 H),7.56 (d,J=8.06 Hz, 2 H), 7.45 (d, J=8.07 Hz, 2 H), 3.13 (t, J=6.97 Hz, 2 H),2.54 (d, J=6.97 Hz, 2 H), 2.13 (quintet, J=7.15 Hz, 2 H); ¹³ C NMR(CDCl₃) δ 199.46, 151.96, 145.20, 138.96, 136.32,135.13, 129.81, 129.39,129.16, 127.77, 38.01, 33.52, 19.68; MS (FAB-LSIMS) 303 M+H!⁺ (C₁₇ H₁₅O₃ Cl, FW=302.76); Anal. C: calcd, 67.44; found, 67.21. H: calcd, 4.99;found, 4.96. Cl: calcd, 11.71; found, 11.74. ##STR316##

EXAMPLE 234

This compound was prepared in a similar manner to Example 1, except thatthe indicated anhydride was used instead ofdihydro-3-(2-methylpropyl)-2,5-furandione. From3,3-tetramethyleneglutaric anhydride:

MP 139°-140° C.; TLC (methylene chloride--5% methanol) R_(f) 0.403; ¹ HNMR (CDCl₃) δ 8.03 (d, J=8.36 Hz, 2H), 7.63 (d, J=8.36 Hz, 2H), 7.55 (d,J=8.36 Hz, 2H), 7.44 (d, J=8.60 Hz, 2H), 3.28 (s, 2H), 2.70 (s, 2H),1.69 (m, 8H); ¹³ C NMR (CDCl₃) δ 200.59, 178.51, 145.09, 138.91, 137.37,135.11, 129.79, 129.44, 129.15, 127.71, 45.79, 43.91, 42.41, 39.26,24.61; MS (FAB-LSIMS) 357 M+H!⁺ (C₂₁ H₂₁ O₃ Cl, FW=356.85); Anal. C:calcd, 70.68; found, 70.73. H: calcd, 5.93; found, 5.89. Cl: calcd,9.93; found, 10.08. ##STR317##

EXAMPLE 235 (Reference with respect to composition)

A dry dichloromethane (10 mL) solution of 4-chlorobiphenyl (0.76 g, 4mmol) and 3-methylglutaric anhydride (0.52 g, 4 mmol) in a 50-mL flaskwas chilled using an ice bath. Solid aluminum chloride (1.1 g, 8 mmol)was cautiously added over several minutes. The reaction mixture wasstirred for 20 hours while warming to room temperature. After 20 hours,the reaction mixture was re-cooled with an ice bath and quenched with10% HCl (10 mL). The layers were separated and the aqueous phase wasback-extracted with dichloromethane (2×10 mL). The combined organicportions were washed with brine (25 mL), dried (Na₂ SO₄), andconcentrated in vacuo. The resulting yellow-white solid wasrecrystallized (ethyl acetate-hexane) to afford white microcrystals ofExample 235: (0.7 g, 56%, mp 140.5°-142.5° C.).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.49; ¹ H-NMR (DMSO-d₆) δ 0.93 (d, J=6.3 Hz, 3H), 2.10 -2.45 (m, 3H),2.85-3.15 (m, 2H), 7.50-8.10 (m, 8H), 12.09 (s, 1H); MS (FAB-LSIMS) 317M+H!⁺ (C₁₈ H₁₇ O₃ Cl, FW=316.79); Anal. C: calcd, 68.25; found, 68.17.H: calcd, 5.41; found, 5.44.

EXAMPLE 236, EXAMPLE 237, EXAMPLE 238, EXAMPLE 239 AND EXAMPLE 240

The syntheses of Example 236, Example 237, Example 238, Example 239, andExample 240 were effected in a manner similar to the method used forExample 235 except that the indicated anhydrides were used instead of3-methylglutaric anhydride. The anhydrides were either commerciallyavailable or synthesized by the routes described below. ##STR318##

EXAMPLE 236

From 3,3-dimethylglutaric anhydride. The crude product was purified byrecrystallization (ethyl acetate-hexane) to afford white microcrystalsof Example 236 (49%, mp 152.0°-154.5° C.):

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.56; ¹ H NMR (DMSO-d₆) δ 1.08 (s, 6H), 2.39 (s, 2H), 3.13 (s, 2H),7.50-8.10 (m, 8H), 11.97 (s, 1H); MS (FAB-LSIMS) 331 M+H!⁺ (C₁₉ H₁₉ O₃Cl, FW=330.81); Anal. C: calcd, 68.98; found, 68.89. H: calcd, 5.79;found, 5.84. ##STR319##

EXAMPLE 237

From 3-ethyl-3-methylglutaric anhydride. The crude product was purifiedby recrystallization (ethyl acetate-hexane) to afford whitemicrocrystals of Example 237 (65%, mp 130.0°-131.0° C.):

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.42; ¹ H NMR (DMSO-d₆) δ 0.79 (t, J=7.4 Hz, 3H), 1.03 (s, 3H), 1.50 (m,2H), 2.39 (m, 2H), 3.12 (m, 2H), 7.50-8.10 (m, 8H), 11.95 (s, 1H); MS(FAB-LSIMS) 345 M+H!⁺ (C₂₀ H₂₁ O₃ Cl, FW=344.84); Anal. C: calcd, 69.66;found, 69.62. H: calcd, 6.14; found, 6.11. ##STR320##

EXAMPLE 238

From 2,2-dimethylglutaric anhydride. The crude product was purified viaflash column chromatography (gradient elution, dichloromethane todichloromethane-methanol (99.5:0.5)) followed by recrystallization(ethyl acetate-hexane) to provide white microcrystals of Example 238(8%, mp 163.5°-164.0° C.):

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.67; ¹ H-NMR (DMSO-d₆) δ 1.14 (s, 6H), 1.81 (m, 2H), 2.98 (m, 2H),7.50-8.10 (m, 8H), 12.21 (s, 1H); MS (FAB-LSIMS) 331 M+H!⁺ (C₁₉ H₁₉ O₃Cl, FW=330.81); Anal. C: calcd, 68.98; found, 68.92. H: calcd, 5.79;found, 5.73.

EXAMPLE 239 ##STR321## Step 1--Preparation of 2-Isobutylglutaric acid

To a 25-mL round-bottomed flask was added diethyl isobutyl malonate(2.82 g, 13 mmol), t-butanol (8.6 mL), and 30% methanolic KOH solution(0.25 mL, 1.3 mmol). Acrylonitrile (0.86 mL, 13 mmol) was added viasyringe and the reaction mixture was heated to 33° C. using an oil bath.After stirring for 3 hours under inert atmosphere the reaction mixturewas quenched with 2M HCl (1 mL) and diluted with distilled water (15 mL)and ether (20 mL). The separated aqueous phase was back-extracted withether (2×20 mL). The combined organic portions were dried (Na₂ SO₄) andconcentrated in vacuo to afford an oil with solid precipitate (3.42 g).This crude material was used in the next step without purification. Aportion of the crude oil and solid (1.5 g) was dissolved in 48% HBr (6mL). The solution was held at reflux under inert atmosphere for 24.5hours after which the solution was concentrated almost to dryness. Theresidue was partitioned between distilled water (20 mL) and ether (20mL). The separated aqueous layer was back-extracted with ether (2×20mL). The combined organic portions were then dried and concentrated invacuo to yield an oily residue (1.5 g). ¹ H-NMR indicated reactioncompletion, so the remaining crude nitrile diester (1.9 g) was subjectedto the above hydrolytic conditions to provide an additional amount ofthe crude substituted glutaric acid (1.5 g). The crude lots werecombined (3.0 g total) and purified via flash column chromatographygradient elution, dichloromethane to dichloromethane-methanol (98:2)! toafford the title compound as a white solid (1.64 g, 69%)I.

¹ H NMR (DMSO-d₆) δ 0.83 (dd, J=6.6 Hz, 2.9 Hz, 6H), 1.16 (m, 1H),1.36-1.56 (m, 2H), 1.61 (q, J=7.4 Hz, 2H), 2.17 (m, 2H), 2.28 (m, 1H),12.11 (s, 2H). ##STR322## Step 2--Preparation of 2-Isobutyl glutaricanhydride

To a 100-mL round-bottomed flask was added the product of step 1(compound 23,1.62 g, 8.6 mmol) and acetic anhydride (10 mL). Thereaction mixture was held at reflux for 2 hours, and then cooled to roomtemperature. Volatiles were removed via vacuum distillation (0.1 Torr,20°-60° C.). The crude product was dried under vacuum (0.1 Torr) at 80°C. for 14 hours to yield the title compound as a brown oil which wasused without further purification (1.15 g, 79%).

¹ H NMR (DMSO-d₆) δ 0.86 (m, 6H), 1.30 (m, 1H), 1.60-1.95 (m, 4H),2.65-2.90 (m, 3H); IR (neat) 1805, 1762 cm⁻¹. ##STR323## Step3--Preparation of Example 239:

From 2-isobutylglutaric anhydride rather than 3-methylglutaric anhydrideand using the general procedure of Example 235. The crude product waspurified via flash column chromatography gradient elution,dichloromethane to dichloromethane-methanol (98.5:1.5)! followed byrecrystallization (ethyl acetate-hexane) to provide white microcrystalsof Example 239 (10%, mp 129.0°-130.5° C.).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.54; ¹ H-NMR (DMSO-d₆) δ 0.85 (dd, J=6.3 Hz, 2.6 Hz, 6H), 1.24 (m, 1H),1.50 (m, 2H), 1.77 (m, 2H), 2.38 (m, 1H), 3.03 (m, 2H), 7.50-8.10 (m,8H), 12.17 (s, 1H); MS (FAB-LSIMS) 359 M+H!⁺ (C₂₁ H₂₃ O₃ Cl, FW=358.87);Anal. C: calcd, 70.29; found, 70.33. H: calcd, 6.46; found, 6.41.

EXAMPLE 240 ##STR324## Ster 1--Preparation of 3,3-Pentamethyleneglutaricanhydride

To a 100-mL round-bottomed flask was added 1,1-cyclohexanediacetic acid(2.03 g, 9.99 mmol) and acetic anhydride (11.6 mL). The reaction mixturewas held at reflux for 2 hours, and then cooled to room temperature.Volatiles were removed via vacuum distillation (0.1 Torr, 20°-60° C.).The resulting crude product was dried under vacuum (0.1 Torr) at 80° C.for 14 hours to yield the title compound as a white solid which was usedwithout further purification (1.75 g, 96%).

¹ H NMR (DMSO-d₆) δ 1.20-1.50 (m, 10H), 2.73 (s, 4H); IR (neat) 1813,1770 cm⁻¹. ##STR325## Step 2--Preparation of Example 240:

From 3,3-pentamethyleneglutaric anhydride rather than 3-methylglutaricanhydride and using the general procedure of Example 235. The crudeproduct was purified via flash column chromatography (gradient elution,dichloromethane to dichloromethane-methanol (97:3)) followed byrecrystallization (ethyl acetate-hexane) to provide white microcrystalsof Example 240 (13%, mp 129.0°-131.5° C.).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.55; ¹ H-NMR (DMSO-d₆) δ 1.20-1.60 (m, 10H), 2.50 (s, 2H), 3.20 (s,2H), 7.50-8.00 (m, 8H), 11.92 (s, 1H); ¹³ C-NMR (DMSO-d₆) δ 199.45,173.52, 143.01, 137.92, 137.34, 133.45, 129.23, 128.96, 128.77, 126.97,43.87, 35.71, 35.39, 25.80, 21.24; MS (FAB-LSIMS) 371 M+H!⁺ (C₂₂ H₂₃ O₃Cl, FW=370.88); Anal. C: calcd, 71.25; found, 71.06. H: calcd, 6.25;found, 6.21.

EXAMPLE 241 ##STR326## Step 1--Preparation of Benzyl-3-bromopropionate

A spatula tip full of p-toluenesulfonic acid monohydrate was added to asolution of 3-bromopropionic acid (20.49 g, 0.134 mol) and benzylalcohol (15 mL, ˜15.7 g, 0.145 mol) in benzene (150 mL). A Dean-Starktrap was fitted to the reaction vessel and the solution was held atreflux with overnight stirring. After 16 hr at reflux, the reaction wascooled, washed with saturated sodium bicarbonate, dried (Na₂ SO₄), andconcentrated to an oil (28.78 g). Fractional distillation at reducedpressure (0.18 torr) gave the desired product as a colorless liquid(18.49 g, 56%) boiling in the range 99°-109° C.

TLC (hexane-ethyl acetate, 3:1): R_(f) 0.72; ¹ H NMR (CDCl₃): δ 2.98 (t,J=6.9 Hz, 2H), 3.61 (t, J=6.9 Hz, 2H), 5.18 (s, 2H), 7.38 (s, 5H).##STR327## Step 2--Preparation of (4'-chlorobiphenyl)cyclopentyl ketone

A dry dichloromethane (50 mL) solution of 4-chlorobiphenyl (3.57 g, 18.9mmol) and cyclopentanecarbonyl chloride (2.6 g, 18.9 mmol) in a 100-mLflask was chilled using an ice bath. Solid aluminum chloride (5 g, 37.7mmol) was cautiously added over several minutes. The reaction mixturewas stirred for 6 hours while warming to room temperature. After 6hours, the reaction mixture was re-cooled with an ice bath and quenchedwith 10% HCl (50 mL). The layers were separated and the aqueous phasewas back-extracted with dichloromethane (2×50 mL). The combined organicportions were washed with brine (100 mL), dried (Na₂ SO₄), andconcentrated in vacuo. The resulting yellow solid was used withoutfurther purification (5.5 g, 100%).

TLC (hexane-ethyl acetate, 3:1): R_(f) 0.22; ¹ H NMR (DMSO-d₆) δ1.50-2.00 (m, 8H), 3.83 (m, 1H), 7.50-8.10 (m, 8H). ##STR328## Step3--Preparation of the Benzyl Ester of Example 241

n-Butyl lithium (2.64M in hexanes, 0.8 mL, 2.16 mmol) was added dropwiseto freshly distilled diisopropylamine (0.3 mL, 0.22 g, 2.16 mmol) inanhydrous tetrahydrofuran (4 mL) at 0° C. and under an argon atmosphere.The solution was stirred for 30 minutes and then cooled to -70° C. Asolution of the product from step 2 (0.59 g, 2.06 mmol) intetrahydrofuran (1 mL, with 0.5 mL rinse) was added via syringe over 20minutes. Stirring was continued for 75 minutes at -70° C. A solution ofbenzyl-3-bromopropionate from step 1 (0.50 g, 2.06 mmol) intetrahydrofuran (1 mL, with 0.5 mL rinse) was added via syringe over 20minutes. The reaction stirred at -70° C. for 1 hour and was then warmedslowly to room temperature overnight. After 14.25 hours of stirringunder inert atmosphere, the reaction mixture was quenched with 10% HCl(10 mL) after dilution with ether (25 mL) and dichloromethane (15 mL).The separated organics were then washed sequentially with 10% HCl (10mL), saturated sodium bicarbonate (2×10 mL), and brine (2×10 mL). Thecombined aqueous washes were then back-extracted with dichloromethane(10 mL). The combined organic phases were dried (Na₂ SO₄) andconcentrated in vacuo to yield an orange-yellow residue which waspurified via flash column chromatography gradient elution,hexane-dichloromethane (1:1) to hexane-dichloromethane (2:3)! to affordthe desired product as an off-white solid (0.18 g, 20%).

TLC (hexane-dichloromethane, 1:1): R_(f) 0.45; ¹ H NMR (DMSO-d₆) δ1.40-2.30 (m, 12H), 4.95 (s, 2H), 7.20-8.00 (m, 13H). ##STR329## Step4--Preparation of Example 241

To a solution of the benzyl ester from step 3 (0.14 g, 0.31 mmol) inabsolute ethanol (0.62 mL) was added a solution of aqueous sodiumhydroxide (1M, 0.46 mL, 0.46 mmol). After stirring for three hours, thereaction mixture was diluted with ethyl acetate (10 mL) and distilledwater (10 mL). The separated aqueous layer was acidified to pH ˜1 withconcentrated HCl and was extracted with ethyl acetate (2×10 mL).Extractions were combined, dried (Na₂ SO₄), and concentrated in vacuo toprovide the product (0.08 g, 73%, mp 161.0°-164.0° C.).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.57; ¹ H NMR (DMSO-d₆) δ 1.40-1.80 (m, 6H), 1.90-2.30 (m, 6H),7.50-8.00 (m, 8H), 12.04 (br s, 1H); MS (FAB-LSIMS) 357 M+H!⁺ (C₂₁ H₂₁O₃ Cl, FW=356.85); HRMS calcd, 356.1179; found, 356.1165.

EXAMPLE 242 ##STR330## Step 1--Preparation of4-(4'-chlorobiphenyl)methylketone

A dry 1,2-dichloroethane (300 mL) solution of 4-chlorobiphenyl (22.64 g,120 mmol) and acetyl chloride (9.6 g, 120 mmol) in a 500-mL flask waschilled using an ice bath. Solid aluminum chloride (17.8 g, 132 mmol)was cautiously added over ten minutes. The reaction mixture was stirredfor 20 hours while warming to room temperature. After 20 hours, thereaction mixture was quenched by slowly adding it to a stirred chilledsolution of 10% HCl (300 mL). Ethyl acetate (200 mL) was added to helpdissolve solids. The layers were separated and the aqueous phase wasback-extracted with ethyl acetate (200 mL). The combined organicportions were washed with brine (300 mL), dried (Na₂ SO₄), andconcentrated in vacuo. The resulting yellow-white solid wasrecrystallized (ethyl acetate-hexane) to provide multiple, crystallinecrops of the desired ketone (25.66 g, 93%).

TLC (hexane-dichloromethane, 2:1): R_(f) 0.61; ¹ H NMR (DMSO-d₆) δ 2.59(s, 3H), 7.50-8.10 (m, 8H).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.49; ¹ H NMR (DMSO-d₆) δ 7.50-8.05 (m, 8H), 13.00 (1H, s); ¹³ C NMR(DMSO-d₆) δ 167.25, 143.11, 138.00, 133.42, 130.19, 129.23, 128.96,126.99; MS (EI) 232 M!⁺ (C₁₃ H₉ O₂ Cl, FW=232.67); Anal. C: calcd,67.11; found, 66.86. H: calcd, 3.90; found, 3.82. ##STR331## Step2--Preparation of Di-tert-butyl methylenemalonate

This compound was prepared and purified according to literatureprecedent (Roberts, et.al., J. Org. Chem, 1983, 48, 3603.) to provide aclear oil (41%).

¹ H NMR (DMSO-d₆) δ 1.43 (s, 18H), 6.19 (s, 2H). ##STR332## Step 3

A dry 100-mL round-bottomed flask was charged with a suspension ofsodium hydride (0.24 g of 95% NaH, ˜9.1 mmol) in dryN,N-dimethylformamide (43 mL) and was cooled to 0° C. A solution of4-(4'-chlorobiphenyl)methylketone from step 1 (2.0 g, 8.67 mmol) inN,N-dimethylformamide (7 mL) was then added via syringe over 15 minutesand stirring was continued for one hour at 0° C. under inert atmosphere.A solution of di-tert-butyl methylenemalonate from above step 2 (1.98 g,8.67 mmol) in N,N-dimethylformamide (5 mL) was added via syringe over 15minutes. After stirring for 15.5 hours with gradual warming to roomtemperature, the reaction mixture was diluted with ether (350 mL) andquenched with 10% HCl (550 mL). The separated aqueous layer was thenback-extracted with ether (100 mL). The combined organics were washedwith brine (2×500 mL). Again, the combined aqueous phases wereback-extracted with ether (100 mL). The combined organic phases weredried (Na₂ SO₄) and concentrated in vacuo to yield an orange solid whichwas purified initially via recrystallization (hexane) to give whitefluffy crystals of the desired product (1.64 g). A significant amount ofthe desired compound remained in the mother liquors and was purified viaflash column chromatography gradient elution, hexane-dichloromethane(1:1) to dichloromethane-methanol (98:2)! to provide additional desiredmaterial as an off-white solid (0.47 g, total 2.11 g, 53%).

TLC (hexane-ethyl acetate, 9:1): R_(f) 0.43; ¹ H NMR (DMSO-d₆) δ 1.38(s, 18H), 2.00 (m, 2H), 3.06 (t, J=7.4 Hz, 2H), 3.30 (m, 1H), 7.50-8.10(m, 8H). ##STR333## Step 4

A dry 25-mL round-bottomed flask was charged with a suspension of sodiummethoxide (0.26 g of 95% NaOMe, ˜4.75 mmol) and the pure product fromstep 3 (2.0 g, 4.36 mmol) in dry dimethoxyethane (4.7 mL).Simultaneously, a dry dimethoxyethane (13.5 mL) suspension of1-bromo-3-phenylpropane (0.67 mL, 0.87 g, 4.36 mmol) and sodium iodide(0.66 g, 4.36 mmol) was formed in a 50-mL round-bottomed flask. Afterstirring 40 minutes under inert atmosphere, the orange enolatesuspension was added via syringe over 10 minutes to the yellowbromide-iodide suspension. After 40 hours of stirring, the reaction wasnot complete as judged by TLC. Additional sodium methoxide (0.13 g, 2.38mmol) and 1-bromo-3-phenylpropane (0.33 mL, 0.44 g, 2.18 mmol) wereadded. After 24 hours of stirring, the reaction mixture was concentratedto dryness. The residue was dissolved in ethyl acetate (50 mL) andquenched with 10% HCl (50 mL). The separated organics were washed with10% HCl (50 mL). Combined aqueous phases were back-extracted withdichloromethane (50 mL). Combined organic phases were dried (Na₂ SO₄)and concentrated in vacuo to yield an orange oil which was purified viaflash column chromatography gradient elution, hexane to hexane-ethylacetate (19:1)! to afford the desired product as an off-white solid(1.66 g, 66%).

TLC (hexane-ethyl acetate, 9:1); R_(f) 0.47; ¹ H NMR (DMSO-d₆) δ1.25-1.50 (m, 20H), 1.74 (m, 2H), 2.04 (m, 2H), 2.57 (t, J=7.0 Hz, 2H),2.81 (m, 2H) 7.10-8.00 (m, 13H); MS (FAB-LSIMS) 577 M+H!⁺ (C₃₅ H₄₁ O₅Cl, FW=577.17). ##STR334## Step 5

A dichloromethane (10 mL) solution of the product from step 4 (1.66 g,2.88 mmol), anisole (7.81 mL, 7.77 g, 71.90 mmol), and trifluoroaceticacid (2.22 mL, 3.28 g, 28.76 mmol) was stirred for 55 hours in a 50-mLround-bottomed flask. The reaction mixture was partitioned between ether(50 mL) and brine (50 mL). Some distilled water was added to solubilizeprecipitating salts. The organic phase was separated, dried (Na₂ SO₄),and concentrated in vacuo to yield a white-pink solid which was purifiedvia flash column chromatography gradient elution, ethylacetate-hexane-acetic acid (25:74:1) to ethyl acetate-hexane-acetic acid(49:50:1)! to afford the desired product as an off-white solid (0.53 g,39%, mp 168.5°-170.0° C.).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.28; ¹ H NMR (DMSO-d₆) δ 1.44 (m, 2H), 1.80 (m, 2H), 2.09 (m, 2H), 2.57(m, 2H), 2.84 (m, 2H), 7.10-8.00 (m, 13H), 12.78 (br s, 2H); ¹³ C NMR(DMSO-d₆) δ 198.74, 173.07, 143.32, 142.03, 137.88, 135.71, 133.55,129.28, 129.01, 128.81, 128.48, 127.12, 125.97, 56.14, 35.40, 33.50,31.63, 26.39, 25.84; MS (FAB-LSIMS) 465 M+H!⁺ (C₂₇ H₂₅ O₅ Cl,FW=464.95); Anal. C: calcd, 69.75; found, 69.66. H: calcd, 5.42; found,5.38. ##STR335## Step 6--Preparation of Example 242

A 1,4-dioxane (7.5 mL) solution of the diacid from step 5 (0.4 g, 0.86mmol) was held at reflux for 44 hours with stirring under inertatmosphere. The reaction mixture was then concentrated to dryness andpurified via flash column chromatography ethyl acetate-hexane-aceticacid (24:75:1)! to afford the title compound as a white solid (0.25 g,69%, mp 97.0°-98.5° C.).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.60; ¹ H-NMR (DMSO-d₆) δ 1.40-1.60 (m, 4H), 1.78 (m, 2H), 2.35 (m, 1H),2.55 (m, 2H), 3.01 (m, 2H), 7.10-8.05 (m, 13H), 12.19 (s, 1H); ¹³ C-NMR(DMSO-d₆) δ 199.13, 176.88, 143.25, 142.15, 137.89, 135.79, 133.50,129.25, 128.98, 128.81, 128.44, 127.09, 125.88, 44.04, 36.03, 35.16,31.48, 28.99, 26.18; MS (EI) 420 M!⁺ (C₂₆ H₂₅ O₃ Cl, FW=420.94); Anal.C: calcd, 74.19; found, 74.08. H: calcd, 5.99; found, 5.88.

EXAMPLE 243 ##STR336## Step 1

A dry dichloromethane (93.5 mL) solution of 4-chlorobiphenyl (7.06 g,37.4 mmol) and γ-methylvaleroyl chloride (5.0 g, 37.4 mmol) in a 250-mLflask was chilled using an ice bath. Solid aluminum chloride (9.97 g,74.8 mmol) was cautiously added over ten minutes. Stirring was continuedfor 23 hours while warming slowly to room temperature. The reactionmixture was quenched by slowly adding it to a stirred chilled solutionof 10% HCl (100 mL). The layers were separated and the aqueous phase wasback-extracted with dichloromethane (2×50 mL). The combined organicportions (cloudy) were washed with brine (50 mL), dried (Na₂ SO₄), andfiltered. Dilution with dichloromethane (100 mL) and finally ethylacetate (100 mL) clarified the solution which was re-dried (Na₂ SO₄) andconcentrated in vacuo to produce a yellow solid (10.33 g). A portion ofthis crude product (2.97 g) was purified via flash column chromatographydichloromethane-hexane (2:3)! to yield the desired product as apale-yellow solid (2.54 g, 82%).

TLC (hexane-ethyl acetate, 9:1): R_(f) 0.54; ¹ H NMR (DMSO-d₆) δ0.85-0.95 (m, 6H), 1.40-1.70 (m, 3H), 3.01, (m, 2H), 7.50-8.10 (m, 8H).##STR337## Step 2

A dry 25-mL round-bottomed flask was charged with a suspension of sodiumhydride (0.044 g of 95% NaH, ˜1.74 mmol) in dry N,N-dimethylformamide(7.9 mL) and was cooled to 0° C. Solid ketone from step 1 (0.5 g, 1.74mmol) was cautiously added to the suspension and stirring was continuedfor one hour at 0° C. under inert atmosphere. A solution ofdi-tert-butyl methylenemalonate from Example 242 step 2 (0.4 g, 1.74mmol) in N,N-dimethylformamide (3 mL) was added via syringe over 15minutes. After stirring for 19 hours with gradual warming to roomtemperature, the reaction mixture was diluted with ether (70 mL) andquenched with 10% HCl (120 mL). The separated organic phase was washedwith brine (2×100 mL), dried (Na₂ SO₄), and concentrated in vacuo toyield a yellow oil. The crude product was purified via flash columnchromatography (gradient elution, hexane-dichloromethane (3:1) tohexane-dichloromethane (1:2)) to afford the desired compound in twofractions, the first slightly contaminated with high R_(f) spots (0.36g, 40%), and the second pure by TLC (0.22 g, 24% (total 64%)).

TLC (hexane-dichloromethane, 1:2): R_(f) 0.20; ¹ H NMR (DMSO-d₆) δ 0.83(dd, J=13.2 Hz, 5.9 Hz, 6H), 1.30-1.60 (m, 21H), 1.80-2.15 (m, 2H), 3.12(dd, J=8.5 Hz, 6.6 Hz, 1H), 3.45-3.65 (m, 1H), 7.50-8.10 (m, 8H).##STR338## Step 3

The two fractions of product from step 2 were reacted separately in thisstep. The order of parenthetical notations of stoichiometry refer to thefirst fraction and the second fraction respectively. Dichloromethane(4.6 mL and 2.9 mL) solutions of each fraction of the product from step2 (0.36 g, 0.7 mmol and 0.22 g, 0.43 mmol ), anisole (1.9 mL, 1.9 g,17.5 mmol and 1.17 mL, 1.16 g, 10.75 mmol), and trifluoroacetic acid(0.54 mL, 0.8 g, 7.0 mmol and 0.33 mL, 0.49 g, 4.3 mmol) were formed inseparate 25-mL round-bottomed flasks. After stirring under inertatmosphere for 22 hours, both reaction mixtures were separatelypartitioned between ethyl acetate (20 mL) and brine (20 mL). Somedistilled water was added to solubilize precipitated salts. Each organicphase was separated, then the two fractions were combined, washed withdistilled water (2×15 mL), dried (Na₂ SO₄), and concentrated in vacuo toyield a faint pink oil which was purified via flash columnchromatography gradient elution, ethyl acetate-hexane-acetic acid(25:74:1) to ethyl acetate-hexane-acetic acid (49:50:1)! to yieldfractions whose ¹ H-NMRs indicated that the reaction had not gone tocompletion. The fractions were recombined and resubjected to thereaction conditions for 16 hours. When the reaction was complete asindicated by TLC, the reaction mixture was worked-up and chromatographedusing the same conditions described above to afford the desired diacidas an off-white solid (0.2 g, 44%).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.17; ¹ H-NMR (DMSO-d₆) δ 0.70-0.90 (m, 6H), 1.20-1.60 (m, 3H),1.80-2.20 (m, 2H), 3.16 (dd, J=8.5 Hz, 6.6 Hz, 1H), 3.60 (m, 1H),7.50-8.10 (m, 8H), 12.83 (br s, 2H). ##STR339## Step 4--Preparation ofExample 243

A 1,4-dioxane (9.1 mL) solution of diacid from step 3 (0.2 g, 0.5 mmol)was held at reflux for 15 hours with stirring under inert atmosphere.The reaction mixture was then concentrated to dryness and purified viaflash column chromatography (dichloromethane-methanol (99:1)) to affordthe title compound as a white solid (0.11 g, 61%, mp 102.0°-103.0° C.).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.48; ¹ H-NMR (DMSO-d₆) δ 0.75-0.90 (m, 6H), 1.20-1.90 (m, 5H), 2.18 (m,2H), 3.67 (m, 1H), 7.50-8.10 (m, 8H), 12.08 (s, 1H); MS (FAB-LSIMS) 359M+H!⁺ (C₂₁ H₂₃ O₃ Cl, FW=358.87); Anal. C: calcd, 70.29; found, 70.23.H: calcd, 6.46; found, 6.46.

EXAMPLE 244 ##STR340## Step 1--Preparation of4-(4'-Chlorobiphenyl)carboxylic acid

Bromine (5.6 mL, 17.3 g, 108.35 mmol) was added to a solution of sodiumhydroxide (15.2 g, 379 mmol) in distilled water (75.8 mL) at 0° C. andwas stirred for 15 minutes. To this reagent mixture was added a solutionof 4-(4'-chlorobiphenyl)methylketone from the Example 242 preparationstep 1 (5.0 g, 21.67 mmol) in 1,4-dioxane (54.2 mL). The reactionmixture was heated for 18 hours at 40° C. using an oil bath and wascooled to room temperature. A solution of sodium thiosulfatepentahydrate (21.5 g, 86.68 mmol) in distilled water (60 mL) was addedto the reaction mixture to quench the remaining bromoform. The mixturewas acidified to pH ˜1 with concentrated HCl (˜25 mL) causing foaming.The solids which precipitated were isolated via filtration andrecrystallized (ethyl acetate) to provide multiple, crystalline crops ofthe title compound (4.44 g, 88%, mp 286.0°-288.0° C.). ##STR341## Step 2

A dry dichloromethane (66 mL) solution of4-(4'-chlorobiphenyl)carboxylic acid from step 1 (3.7 g, 15.9 mmol),N,O-dimethylhydroxylamine hydrochloride (2.34 g, 23.85 mmol), and1-hydroxybenzotriazole (2.36 g, 17.49 mmol) in a 100-mL round-bottomedflask was chilled using an ice bath and stirred for a few minutes.N-methylmorpholine (2.62 mL, 2.41 g, 23.85 mmol) was added quickly viasyringe followed by solid 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(3.36 g, 17.49 mmol). The reaction mixture was stirred for several hoursat 0° C. under inert atmosphere. Stirring was continued while warming toroom temperature overnight. After a total of 23 hours of stirring, thereaction was incomplete as judged by TLC. Dry N,N-dimethylformamide (2mL) was added at 0° C. to clarify the reaction mixture. TLC after 1 hourshowed no further conversion, so additional reagents were addedN,O-dimethylhydroxylamine hydrochloride (0.46 g), 1-hydroxybenzotriazole(0.47 g), N-methylmorpholine (0.52 mL), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.66 g)! at 0° C. TLCafter 3 more hours indicated complete conversion so the reaction mixturewas diluted with dichloromethane (200 mL) and washed sequentially withsaturated sodium bicarbonate (2×100 mL), 10% HCl (100 mL), and saturatedsodium bicarbonate (100 mL). The combined aqueous portions wereback-extracted with ether (50 mL). The combined organic phases weredried (Na₂ SO₄) and concentrated in vacuo to yield an orange solid whichwas purified via flash column chromatography (gradient elution,dichloromethane to dichloromethane-methanol (99.5:0.5)) to afford thedesired product as a white solid (3.89 g, 89%).

TLC (dichloromethane): R_(f) 0.27; ¹ H NMR (DMSO-d₆) δ 3.26 (s, 3H), 253.55 (s, 3H), 7.50-7.80 (m, 8H); MS (FAB-LSIMS) 276 M+H!⁺ (C₁₅ H₁₄ O₂NCl, FW 275.74). ##STR342## Step 3

n-Butyl lithium (2.64M in hexanes, 10.2 mL, 26.98 mmol) was addeddropwise to freshly distilled diisopropylamine (3.78 mL, 2.73 g, 26.98mmol) in anhydrous tetrahydrofuran (50 mL) at -40° C. and under an argonatmosphere. The solution was stirred for 25 minutes with warming to -20°C. and then cooled to -40° C. A solution of 5-phenylvaleric acid (2.40g, 13.49 mmol) in tetrahydrofuran (4 mL, with 1 mL rinse) was added viasyringe over 7 minutes causing precipitation of a solid. The stirredsolution was heated at 50° C. for 2 hours and was then re-cooled to -40°C. A solution of the product from step 2 (3.1 g, 11.24 mmol) intetrahydrofuran (4 mL, with 1 mL rinse) was added via syringe over 8minutes. The reaction stirred at -40° C. for 3 hours and was thenquenched by cautious decanting into 10% HCl (50 mL). The mixture wasextracted with ether (150 mL). The separated aqueous phase wasback-extracted with ethyl acetate (2×50 mL). The combined organic phaseswere washed with brine (75 mL), dried (Na₂ SO₄), and concentrated invacuo to provide an orange solid which was then purified via flashcolumn chromatography (gradient elution, hexane-dichloromethane (3:1) tohexane-dichloromethane (3:2)) to afford the desired product as ayellow-white solid (1.80 g, 46%):.

TLC (hexane-dichloromethane, 1:2): R_(f) 0.75; ¹ H NMR (DMSO-d₆) δ 1.62(m, 4H), 2.60 (m, 2H), 3.05 (m, 2H), 7.10-8.10 (m, 13H); MS (FAB-LSIMS)349 M+H!⁺ (C₂₃ H₂₁ O₃ Cl, FW=348.88). ##STR343## Step 4

A dry 50-mL round-bottomed flask was charged with a suspension of sodiumhydride (0.15 g of 95% NaH, ˜5.8 mmol) in dry N,N-dimethylformamide (20mL) and was cooled to 0° C. A solution of the ketone product from step 3(1.93 g, 5.53 mmol) in N,N-dimethylformamide (10 mL) was added viasyringe over 10 minutes. Stirring was continued for one hour at 0° C.under inert atmosphere. A solution of the di-tert-butylmethylenemalonate from the Example 242 preparation step 2 (1.26 g, 5.53mmol) in N,N-dimethylformamide (3 mL) was added via syringe over 4minutes to the dark orange reaction mixture. After stirring for 15 hourswith gradual warming to room temperature, the reaction mixture wasdiluted with ether (300 mL) and quenched with 10% HCl (500 mL). Theseparated organic phase was washed with brine (2×500 mL), dried (Na₂SO₄), and concentrated in vacuo to yield a yellow oil which was purifiedvia flash column chromatography gradient elution, hexane-dichloromethane(4:1) to hexane-dichloromethane (1:1)! to yield the desired material asan off-white solid (2.13 g, 67%).

TLC (hexane-dichloromethane, 1:2): R_(f) 0.64; ¹ H NMR (DMSO-d₆) δ 1.32(d, J=5.9 Hz, 18H), 1.35-1.70 (m, 4H), 1.80-2.15 (m, 2H), 2.51 (m, 2H),3.05-3.15 (m, 1H), 3.45-3.60 (m, 1H) 7.00-8.00 (m, 13H); MS (FAB-LSIMS)577 M+H!⁺ (C₃₅ H₄₁ O₅ Cl, FW=577.17). ##STR344## Step 5--Preparation ofExample 244

A dichloromethane (15 mL) solution of the product from step 4 (2.1 g,3.64 mmol), anisole (9.9 mL, 91 mmol), and trifluoroacetic acid (2.8 mL,36.4 mmol) was stirred in a 50-mL round-bottomed flask. After 72 hours,the reaction had not gone to completion. Additional trifluoroacetic acid(5 mL, 65 mmol) was added. After stirring for an additional 4.5 hoursthe reaction mixture was partitioned between ethyl acetate (75 mL) andbrine (75 mL). Some distilled water was added to solubilize precipitatedsalts. The organic phase was separated, dried (Na₂ SO₄), andconcentrated in vacuo to yield an orange-brown oil which was purifiedvia flash column chromatography gradient elution, ethylacetate-hexane-acetic acid (25:74:1) to ethyl acetate-hexane-acetic acid(49:50:1)! to afford the desired diacid plus decarboxylated compound(after vacuum oven drying) as a white solid (1.35 g, ˜80%, mp45.0°-51.0° C. (dec.)): TLC (chloroform-methanol, 9:1 with trace amountof acetic acid): R_(f) 0.34. A 1,4-dioxane (18 mL) solution of a portionof the partially converted diacid (1.0 g, ˜2.15 mmol) was held at refluxfor 20 hours with stirring under inert atmosphere. The reaction mixturewas then concentrated to dryness and purified via flash columnchromatography (ethyl acetate-hexane-acetic acid (19:80:1))to afford thetitle compound as a clear gum (0.75 g, 83%).

TLC (chloroform-methanol, 9:1 with trace amount of acetic acid): R_(f)0.62; ¹ H NMR (DMSO-d₆) δ 1.40-2.20 (m, 8H), 2.52 (m, 2H), 3.64 (m, 1H),7.00-8.10 (m, 13H), 12.09 (br s, 1H); ¹³ C NMR (DMSO-d₆) δ 203.24,174.29, 143.47, 141.99, 137.86, 136.08, 133.56, 129.26, 129.04, 128.42,127.29, 125.89, 44.16, 35.27, 31.56, 28.83, 26.97; MS (FAB-LSIMS) 421M+H!⁺ (C₂₆ H₂₅ O₃ Cl, FW=420.94); Anal. C: calcd, 74.19; found, 73.95.H: calcd, 5.99; found, 5.82.

EXAMPLE 245 ##STR345## Step 1

A solution of p-bromobiphenyl (20.0 g, 0.0858 mol) and α-bromoacetylbromide (7.5 mL, 0.0858 mol, 1.0 equiv.) in CH₂ Cl₂ (400 mL) under argonwas cooled to 0° C. and AlCl₃ (24.0 g, 0.180 mol, 2.1 equiv) was addedin four parts. The resulting dark green solution was allowed to slowlywarm to room temperature, then stirred for 14 h. The reaction was thencooled to 0° C. and quenched with a 10% HCl solution (200 mL). Theresulting aqueous layer was separated and extracted with CH₂ Cl₂ (3×100mL). The combined organic layers were washed with a saturated NaClsolution (150 mL), dried (anh. MgSO₄) and concentrated under reducedpressure to afford a brown solid (29.3 g, 96%) which was used in thenext step without further purification ##STR346## Step 2

A slurry of the intermediate from step 1 (29.3 g, 0.0827 mol) and PPh₃(23.9 g, 0.0910 mol, 1.1 equiv.) in dry THF (400 mL) way heated at thereflux temperature for 14 h. The resulting solids were removed byfiltration and washed with diethyl ether to give the phosphonium bromide(46.7 g, 92%). A mixture of the bromide (7.60 g, 1.23 mmol), CH₂ Cl₂ (50mL) and a 10% NaOH solution (20 mL) was vigorously stirred for 30 min.The aqueous layer was extracted with CH₂ Cl₂ (30 mL) and the combinedorganics were washed with H₂ O (30 mL) and dried (anh. MgSO₄). Theresulting solids were triturated with EtOAc to give the desired ylid asa light brown powder (5.17 g, 78%) which was used in the next step: TLCR_(f) (EtOAc) 0.55. ##STR347## Step 3

To a solution of N-methylmorpholine oxide (11.4 g, 0.0973 mol, 1.40equiv.) in CH₂ Cl₂ (200 mL) was added 4-phenylbutanol (10.2 mL, 0.0696mol) and powdered 4 Å seives (2.0 g). After stirring for 10 min.,tetrapropylammonium perruthenate (0.218 g, 6.20 mmol. 9 mol %), and theresulting mixture was allowed to stir for 48 h. The reaction mixture wasfiltered through Florisil® with the aid of CH₂ Cl₂ (200 mL) and theresulting solution was washed with a saturated Na₂ SO₃ solution (200mL), a saturated NaCl solution (200 mL), a 1M CuSO₄ solution (200 mL)and dried (anh. MgSO₄). Concentration under reduced pressure followed bybulb-to-bulb distillation afforded the desired aldehyde as a colorlessoil (9.3 g, 90%), which slowly oxidized on exposure to air.

TLC R_(f) (25% EtOAc/hexane) 0.60; ¹ H NMR (CDCl₃) δ 1.98 (pent, J=7.44Hz, 2H), 2.46 (td, J=7.35, 2.46 Hz, 2H), 2.67 (t, J=7.54 Hz, 2H),7.17-7.33 (m, 5H), 89.77 (t, J=1.66 Hz, 1H). ##STR348## Step 4

A mixture of compound from step 2 (12.5 g, 0.0233 mol) and compound fromstep 3 (4.13 g, 0.0280 mol, 1.5 equiv.) in dry THF (230 mL) were heatedat the reflux temperature for 80 h. The resulting mixture wasconcentrated under reduced pressure, dissolved in acetone (250 mL),cooled to 0° C. and treated dropwise with Jones reagent until allstarting aldehyde was consumed as shown by TLC analysis. The acetonemixture was concentrated under reduced pressure, dissolved in EtOAc (250mL), washed with a saturated NaHCO₃ solution (150 mL), and dried (anh.MgSO₄). The resulting solution was concentrated under reduced pressure,dissolved in CH₂ Cl₂, and filtered through a small pad of SiO₂ with theaid of 25% EtOAc/hexane to remove remaining 4-phenylbutyric acid and Ph₃PO to afford the desired enone as a single diastereomer (3.85 g, 41%).

TLC R_(f) (25% EtOAc/hexane) 0.68. Anal. Calcd for C₂₄ H₂₁ BrO: C,71.05; H, 5.22; O, Br; 19.71. Found: C, 70.77; H, 5.23; O, 19.56.##STR349## Step 5

To a solution of the product from step 4 (0.405 g, 1.00 mmol) and aceticacid (0.060 mL, 1.0 mmol, 1.0 equiv) in abs. EtOH (15 mL) at 35° C. wasslowly added a solution of KCN (0.130 g, 2.00 mmol, 2.0 equiv.) in H₂ O(1.2 mL). The mixture was stirred at 35° C. for 14 h and the resultingslurry was separated between CHCl₃ (50 mL) and H₂ O (50 mL). The aqueouslayer was extracted with CHCl₃ (2×20 mL), and the combined organics werewashed with H₂ O (3×40 mL), dried (anh. MgSO₄) and concentrated underreduced pressure. The resulting solids were recrystallized usingEtOAc/hexane to afford the cyano product as a white powder (0.252 g,58%).

MP 139°-141° C.; TLC R_(f) (25% EtOAC/hexane) 0.46; ¹ H NMR (CDCl₃) δ1.74 (tt, J=6.98, 6.98 Hz, 2H), 1.84-2.01 (m, 2H), 2.67-2.74 (m, 2H),3.23 (dd, J=16.54, 6.26 Hz, 1H), 3.33 (dddd, J=6.25, 6.25, 6.25, 6.25Hz, 1H), 3.43 (dd, J=16.55,6.25 Hz, 1H), 7.19-7.39 (m, 3H), 7.31-7.33(m, 2H), 7.50 (app d, J=8.46 Hz, 2H), 7.61 (app d, J=8.82 Hz, 2H), 7.67(app d, J=8.46 Hz, 2H), 8.01 (app d, J=8.83 Hz, 2H); ¹³ C NMR (CDCl₃) δ26.3, 28.8, 31.4, 35.1, 40.8, 121.7, 122.9,

126.0, 127.2 (2C), 128.4 (2C), 128.5 (2C), 128.7 (2C), 128.8 (2C), 132.2(2C), 134.8, 138.4, 141.2, 145.2, 194.7; MS (FAB-LSIMS; rel abund.) 432(40%, M(⁷⁹ Br)+H!⁺), 434 (40%, M(⁸¹ Br)+H!⁺). HRMS (FAB) Calcd for C₂₅H₂₃ ⁷⁹ BrNO M+H!⁺ : 432.09630. Found: 432.09552. Anal. Calcd for C₂₅ H₂₂BrNO: C, 69.44; H, 5.13; Br, 18.48; N, 3.24. Found: C, 69.18; H, 5.26;Br, 18.51; N, 3.03. ##STR350## Step 6--Preparation of Example 245:

A mixture of the product of step 5 and trimethyltin azide (0.180 g,0.874 mmol, 2.00 equiv.) in toluene (25 mL) was heated at 105° C. for 60h, after which volatiles were removed at 105° C. to afford thetrimethylstannyl tetrazole as a single compound. The foamy brown solidswere redissolved in toluene (10 mL) and treated with HCl (4.0M indioxane, 0.33 mL, 1.32 mmol, 3.02 equiv.). The resulting mixture wasstirred at room temperature for 14 h, then separated between EtOAc (50mL) and H₂ O (50 mL). The organic phase was washed with H₂ O (2×50 mL)and a saturated NaCl solution (2×50 mL) and concentrated to give thedesired tetrazole as a yellow solid (0.211 g, 100%).

MP 175°-180° C. (dec); ¹ H NMR (CD₃ OD) δ 1.35-1.55 (m, 2H), 1.75-1.80(m, 2H), 2.30 (br s, 1H), 2.30-2.60 (m, 2H), 3.45-3.80 (m, 3H), 7.10-7.2(m, 2H), 7.72 (br s, 4H), 7.81, D, J=8.85 Hz, 2H), 8.02 (d, J=8.84 Hz,2H) (the ¹ H NMR also shows a minor amount of a second tetrazole N-Hdiastereomer); ¹³ C NMR (CD₃ OD) δ 28.4, 30.0, 33.5, 34.8, 41.8, 122.1,125.8, 126.9 (2C), 128.3 (4C), 128.8 (2C), 129.1 (2C), 132.0 (2C),135.4, 138.0, 141.8, 143.4, 167.4, 197.4; MS (FAB-LSIMS; rel abund.) 475(10%, M(⁷⁹ Br)+H!⁺), 477(9%, M(⁸¹ Br)+H!⁺). HRMS (FAB) Calcd for C₂₅ H₂₄⁷⁹ BrN₄ O M+H!⁺ : 475.1132. Found: 475.1120.

EXAMPLE 246 ##STR351## Step 1

To a mixture of diethyl phosphite (2.8 mL, 0.0217 mol) and triethylamine(9. mL, 0.065 mol, 3.0 equiv.) in dry diethyl ether (250 mL) at 0° C.was slowly added freshly distilled trimethylsilyl chloride (3.3 mL,0.0260 mol, 1.2 equiv.) via syringe. The resulting slurry was allowed toslowly warm to room temperature, and was then warmed to 45° C. for 14 h.Volatiles were removed by distillation using a 55° C. oil bath. Theresulting mixture was diluted with pentane (150 mL), filtered to removetriethylammonium salts, and concentrated at atmospheric pressure using a55° C. oil bath. Distillation of the resulting oil gave diethyltrimethylsilyl phosphite as a colorless oil (3.64 g, 80%).

BP 60° C. (5 mmHg); ³¹ P NMR (CDCl₃) δ 8.27 (s). ##STR352## Step 2

A slurry of product from step 4 of the Example 245 preparation (0.200 g,0.490 mmol) and diethyl trimethylsilyl phosphite (0.105 g, 0.490 mmol,1.0 equiv.) in a dry NMR tube under argon was dissolved using a 50° C.sonicator bath, then heated at 50° C. for 14 h. This was concentratedunder reduced pressure and treated with an additional portion of diethyltrimethylsilyl phosphite (0.5 mL) and heated at 50° C. for 24 h. Thereaction mixture was concentrated under reduced pressure, dissolved inCDCl₃ (which apparently cleaved the silyl enol ether), concentratedunder 1 mmHg at 50° C. for 3 h to afford the above diethyl ester as aviscous, slightly yellow oil (0.23 g, 95%).

¹ H NMR (CDCl₃) δ; MS (FAB-LSIMS; rel abund.) 543 (92%, M(⁷⁹ Br)+H!⁺),545(100%, M(⁸¹ Br)+H!⁺). Anal. Calcd for C₂₈ H₃₂ BrO₄ P: C, 61.83; H,5.94. Found: C, 62.05; H, 6.11. ##STR353## Step 3--Preparation ofExample 246.

To a solution of the product from step 2 (0.243 g, 0.490 mmol) in dryCH₂ Cl₂ (15 mL) was added trimethylsilyl bromide (0.48 mL, 3.64 mmol,7.4 equiv.) via syringe. This was allowed to stir at room temperaturefor 14 h. The resulting solution was then concentrated to approximately8 mL under reduced pressure then treated with MeOH (10 mL). Thisconcentration/dilution regimen was repeated five more times, after whichthe reaction mixture was concentrated under reduced pressure. Theresulting solids were triturated with hexanes to afford the desiredphosphonic acid (0.150 g, 63%).

MP 150°-152° C.; ¹ H NMR (CD₃ OD) δ 1.50-1.65 (m, 1H), 1.65-1.85 (m,2H), 1.85-1.97 (m, 1H), 2.15-2.35 (m, 2H), 2.72-2.84 (m, 1H), 3.15-3.32(m, 1H), 7.08-7.11 (m, 3H), 7.19 (app d, j=6.99 Hz, 2H), 7.44 (app d,J=8.45 Hz, 2H), 7.55 (app d, J=8.46 Hz, 2H), 7.63 (app d, J=8.45 Hz,2H), 8.01, (app d, J=8.09 Hz, 2H); ¹³ C NMR (CD₃ OD) δ 28.9 (d, J=2.44Hz, 1C), 29.9 (d, J=9.76 Hz, 1C), 31.4 (d, J=142.83 Hz, 1C), 37.0 (d,J=33.07 Hz, 1C), 50.9, 120.3, 123.5, 126.6, 127.9 (2C), 129.0 (4C),129.5 (2C), 129.7 (2C), 132.8 (2C), 135.6, 139.0, 142.2, 145.9, 198.9(d, J=11.0 Hz, 1C); ³¹ P NMR (CDCl₃) δ 35.5 (s); MS (FAB-LSIMS; relabund.) 487 (100%, M(⁷⁹ Br)+H!⁺), 489 (92%, M(⁸¹ Br)+H!⁺). Anal. Calcdfor C₂₄ H₂₄ BrO₄ P.H₂ O: C, 57.04; H, 5.19; Br, 15.81; P, 6.13. Found:C, 56.69; H, 5.98; Br, 15.98; P, 6.16. ##STR354##

EXAMPLE 247

A dry dichloromethane (3 mL) solution of Example 1 (0.25 g, 0.725 mmol),proline N-methyl amide hydrochloride (0.48 g, 2.90 mmol), and1-hydroxybenzotriazole (0.10 g, 0.725 mmol) in a 10-mL round-bottomedflask was chilled using an ice bath and stirred for a few minutes.N-methylmorpholine (0.32 mL, 0.29 g, 2.90 mmol) was added quickly viasyringe followed by solid 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(0.146 g, 0.76 mmol). The reaction mixture was stirred under argon forseveral hours at 0° C. and was then warmed to room temperatureovernight. The reaction mixture was then diluted with chloroform (30 mL)and washed with 10% HCl (10 mL). The separated aqueous layer wasback-extracted with chloroform (5 mL). The combined organic portionswere washed with saturated NaHCO₃ (10 mL), dried (Na₂ SO₄), andconcentrated in vacuo. The crude oil was purified via flash columnchromatography dichloromethane-methanol (98:2)! to provide the titlecompound as a white solid (0.26 g, 79%, mp 75.5°-78.0° C.).

TLC (dichloromethane-methanol, 94:6): R_(f) 0.73; ¹ H NMR (DMSO-d₆) δ0.60-1.00 (m, 6H), 1.20-2.00 (m, 7H), 2.50-2.60 (m, 3H), 2.60-5.00 (m,6H), 7.00-8.20 (m, 9H); MS (FAB-LSIMS) 455 M+H!⁺ (C₂₆ H₃₁ O₃ N₂ Cl,FW=455.00); HRMS calcd, 454.2023; found, 454.2030.

EXAMPLE 248 ##STR355## Step 1

A solution of 2,4'-dibromoacetophenone (0.62 g, 2.19 mmoles) andacetamide (0.20 g, 3.32 mmoles) in 6 mL of toluene was refluxed for 3days. The solvent was removed at reduced pressure and the residue waschromatographed with 0-30% ethyl acetate in hexanes to afford 0.20 mg(38%) of product as a white solid.

TLC (methylene chloride) R_(f) 0.42; ¹ H NMR (CDCl₃) δ 7.81 (s, 1H),7.59 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.9 Hz, 2H), 2.52 (s, 3H); ¹³ C NMR(CDCl₃) δ 162.01, 139.71, 133.33, 131.81, 130.07, 126.90, 121.64, 13.94.##STR356## Step 2

A solution of trimethyltin chloride (0.81 g, 4.06 mmoles) in DME (1.5mL) was added to a stirred suspension of small cubes of metallic sodium(0.3 g, 13.05 mmoles) in DME (2.5 mL) under a stream of argon in an icecold round bottom flask. The mixture was stirred in the ice bath for 3.5hrs when the mixture turned green. The mixture was syringed into acooled round bottom flask and treated with a solution of the product ofstep 1 (0.8 g, 3.36 mmoles) in DME (4 mL). T he reaction mixture wasthen allowed to warm and stir at room temperature overnight. At thistime, it was diluted with ethyl acetate, washed with water, brine, anddried over MgSO₄. The crude product was chromatographed with 3-20% ethylacetate in hexanes to afford 0.76 g (70%) of product as an oil.

TLC (hexanes--20% ethyl acetate) R_(f) 0.37; ¹ H NMR (CDCl₃) δ 7.80 (s,1H), 7.66 (d, J=8.05 Hz, 2H), 7.51 (d, J 8.05, 2H), 2.50 (s, 3H), 0.28(s, 9H). ##STR357## Step 3

A solution of the product of step 2 (0.21 g, 0.65 mmole), the acidchloride from step 3 of the Example 61 preparation (0.16 g, 0.74 mmole),and PdCl₂ (PPh₃)₂ (0.078 g, 0.14 mmole) in 1,2-dichloroethane (1.5 mL)was refluxed overnight. The reaction mixture was diluted with ethylacetate and filtered. The filtrate was concentrated at reduced pressureand chromatographed with 3-50% ethyl acetate in hexanes to afford 66 mgof product as a solid.

TLC (hexanes--20% ethyl acetate) R_(f) 0.17; ¹ H NMR (CDCl₃) δ 7.98 (d,J=8.9 Hz, 2H), 7.90 (s, 1H), 7.78 (d, J=8.6 Hz, 2H), 4.14 (q, J=6.6 Hz,2H), 3.42 (q, J=8.3 Hz, 1H), 3.12-2.99 (m, 2H), 2.53 (s, 3H), 1.67-1.58(m, 2H), 1.45-1.34 (m, 1H), 1.24 (t, J=7.5 Hz, 3H), 0.96 (d, J=6.3 Hz,3H), 0.90 (d, J=6.3 Hz, 3H); ¹³ C NMR (CDCl₃) δ 197.66, 175.98, 162.30,139.73, 135.88, 135.61, 134.59, 128.63, 125.34, 60.46, 41.50, 40.89,38.66, 25.93, 22.64, 22.29, 14.19, 13.95; MS (FAB-LSIMS) 344 M+H!⁺ ;HRMS (FAB) calcd. for C₂₀ H₂₆ NO₄ M+H!⁺ 344.18618, Found 344.18600.##STR358## Step 4--Preparation of Example 248

The product of step 3 (56 mg, 0.16 mmole) was suspended in ethanol (1.3mL) and treated with 4N NaOH (0.4 mL). The mixture was stirred at roomtemperature overnight. The reaction mixture was then quenched with 2NHCl, diluted with ethyl acetate, and the layers were separated. Theorganic layer was washed with brine and dried over MgSO₄. The productwas chromatographed with 0-12% methanol in methylene chloride to afford40 mg (78%) of Example 248 as a solid.

MP 120° C.; TLC (methylene chloride--10% methanol) R_(f) 0.32; ¹ H NMR(CDCl₃) δ 8.00 (d, J=8.2 Hz, 2H), 7.91 (s, 1H), 7.79 (d, J=8.2 Hz, 2H),3.43 (dd, J₁ =17.1 Hz, J₂ =7.9 Hz, 1H), 3.17-3.04 (m, 2H), 2.55 (s, 3H),1.75-1.65 (m,2H), 1.44-1.39 (m,1H), 0.98 (d, J=6.2 Hz, 3H), 0.93 (d,J=6.2 Hz, 3H); ¹³ C NMR (CDCl₃) δ 197.43, 180.62, 162.38, 139.71,135.72, 135.69, 134.64, 128.66, 125.39, 41.13, 40.65, 38.26, 25.89,22.53, 22.30, 13.92; MS (FAB-LSIMS) 316 M+H!⁺ ; HRMS (FAB) calcd. forC₁₈ H₂₂ NO₄ M+H!⁺ 316.15488, Found 316.15424; Elemental Analysis: calcd.C 68.55, H 6.71, N 4.44; found C 68.35, H 6.70, N 4.31. ##STR359##

EXAMPLE 249

The procedure was analogous to that of Example 248 except thioacetamidewas used instead of acetamide.

TLC (methylene chloride--10% methanol) R_(f) 0.44; ¹ H NMR (CDCl₃) δ7.92 (broad s, 4H), 7.39 (broad s, 1H), 3.35 (m, 1H), 3.00 (m, 2H), 2.72(s, 3H), 1.64 (m, 2H), 1.35 (m, 1H), 0.91 (broad s, 3H), 0.86 (broad s,3H); ¹³ C NMR (CDCl₃) δ 197.53, 180.49, 166.58, 153.74, 138.69, 135.64,128.66, 126.34, 114.60, 41.12, 40.69, 38.22, 25.87, 22.53, 22.28, 19.25;MS (FAB-LSIMS) 332 M+H!⁺ ; HRMS (FAB) calcd. for C₁₈ H₂₂ NO₃ S M+H!⁺332.13204, Found 332.13287.

EXAMPLE 250 ##STR360## Step 1

A solution of 2-acetyl-5-bromothiophene (0.55 g, 2.64 mmoles) in toluene(5 mL) was treated with Pd(PPh₃)₄ and allowed to stir at roomtemperature for 30 min. at which time 4-chlorobenzeneboronic acid (0.46g, 2.91 mmoles) and NaOMe in MeOH (1.21 mL, 25% wt, 5.29 mmoles) wereadded. The reaction mixture was then refluxed for 4 hrs. The mixture wascooled to room temperature and 2N NaOH (3 mL) was added and stirring wascontinued for another 2 hrs. The mixture was then diluted with methylenechloride, washed with brine and dried over MgSO₄. The crude product waschromatographed with 0-30% ethyl acetate in hexanes to afford 0.51 g(82%) of product.

TLC (hexanes--10% ethyl acetate) R_(f) 0.24; ¹ H NMR (CDCl₃) δ 7.66 (d,J=3.6 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.9 Hz, 2H), 7.30 (d,J=3.9 Hz, 1H), 2.58 (s, 3H); ¹³ C NMR (CDCl₃) δ 190.55, 151.24, 143.46,134.96, 133.41, 131.83, 129.33, 127.45, 124.19, 26.56. ##STR361## Step 2

The product of step 1 (0.51 g, 2.17 mmoles) was dissolved in THF (10mL), cooled to 0° C., and treated with phenyltrimethyl-ammoniumtribromide (0.84 g, 2.17 mmoles). The reaction mixture was then stirredat room temperature for 5 hrs. The mixture was quenched with H₂ O andextracted with ethyl acetate (2×15 mL). The extracts were washed withbrine and dried over MgSO4 to afford 0.62 g (91%) crystallized fromether/hexanes.

TLC (hexanes--10% ethyl acetate) R_(f) 0.27; ¹ H NMR (CDCl₃) δ 7.77 (d,J=3.9 Hz, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.33 (d,J=3.8 Hz, 1H), 4.36 (s, 2H); ¹³ C NMR (CDCl₃) δ 184.20, 152.82, 139.60,135.41, 134.56, 131.46, 129.42, 127.57, 124.43, 30.12. ##STR362## Step 3

A solution of 3-phenyl-propyl diethyl malonate (0.85 g, 3.05 mmoles) inTHF (10 mL) was treated with NaH (0.068 g, 2.81 mmoles) under a streamof argon. The solution was stirred at room temperature for 30 min. Atthis time, a solution of the product of step 2 (0.62 g, 1.98 mmoles) inTHF (14 mL) was added dropwise. After the addition, the reaction mixturewas stirred at room temperature for 15 min when it was quenched with H₂O, diluted with ethyl acetate, and the layers were separated. Theorganic layer was washed with brine, dried over MgSO₄. The residue wasthen chromatographed with 0-40% ethyl acetate in hexanes to afford 0.63g of product.

TLC (hexanes--20% ethyl acetate) R_(f) 0.39; ¹ H NMR (CDCl₃) δ 7.70 (d,J=4.2 Hz, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.30 (d,J=3.9 Hz, 1H), 7.25-7.11 (m, 5H), 4.20 (q, J=6.9 Hz, 4H), 3.59 (s, 2H),2.61 (t, J=7.5 Hz, 2H), 2.20-2.13 (m, 2H), 1.65-1.55 (m, 2H), 1.23 (t,J=6.8 Hz, 6H). ##STR363## Step 4

A solution of the product of step 3 (0.63 g, 1.23 mmoles) in ethanol (5mL) was treated with sodium hydoxide (0.24 g, 6.16 mmoles) in H₂ O (0.5mL) and the mixture was stirred at room temperature for 2 hrs. At thistime, the reaction mixture was acidified with 2N HCl, diluted with ethylacetate, and the layers were separated. The organic layer was washedwith brine and dried over MgSO₄ to afford 0.54 g of the diacid productafter decolorizing with activated carbon.

TLC (methylene chloride--10% methanol) R_(f) 0.13; ¹ H NMR (CDCl₃/DMSO-d₆) δ 7.63 (d, J=3.9 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.32 (d,J=8.3 Hz, 2H), 7.23 (d, J=4.2 Hz, 1H), 7.20-7.06 (m, 5H), 3.63 (s, 2H),2.59-2.50 (m, 2H), 1.97-1.91 (m, 2H), 1.69-1.61 (m, 2H). ##STR364## Step5--Preparation of Example 250

The product of step 4 (50 mg, 0.11 mmoles) was dissolved in dryacetonitrile (1.5 mL) and treated with copper oxide (2 mg, 0.014 mmole).The mixture was refluxed for 36 hrs under a stream of argon. At thistime, it was diluted with ethyl acetate and quenched with 2N HCl. Thelayers were separated, and the organic was washed with brine and driedover MgSO₄ to afford 34 mg of Example 250 crystallized fromether/hexanes.

EXAMPLE 250

MP 149° C.; TLC (methylene chloride--10% methanol) R_(f) 0.40; ¹ H NMR(CDCl₃) δ 7.69 (d, J=3.6 Hz, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.6Hz, 2H), 7.30-7.16 (m, 6H), 3.37 (dd, J₁ =16.7 Hz, J₂ =8.3 Hz, 1H),3.16-3.11 (m, 1H), 3.00 (dd, J₁ =16.7 Hz, J₂ =4.5 Hz, 1H), 2.69-2.63 (m,2H), 1.84-1.66 (m, 4H); ¹³ C NMR (CDCl₃) δ 190.61, 179.33, 151.40,142.42, 141.73, 135.04, 133.09, 131.75, 129.34, 128.36, 127.48, 125.89,124.24, 40.23, 39.89, 35.58, 31.35, 28.81; MS (FAB-LSIMS) 413 M+H!⁺ ;Elemental Analysis calcd. for C₂₃ H₂₁ ClO₃ S C 66.90, H 5.13, Cl 8.59, S7.76; Elemental Analysis found. C 67.00, H 5.28, Cl 8.40, S 7.85.

EXAMPLE 251 ##STR365## Step 1

The methyl ester of 5-bromofuroic acid (204 mg, 0.99 mmole) wasdissolved in DME (3.5 mL) followed by the addition of Pd(OAc)₂ (24 mg,0.11 mmole), P(o-tolyl)₂ (60 mg, 0.20 mmole), 4-chlorobenzeneboronicacid (168 mg, 1.07 mmoles), and sodium carbonate (1.0 mL, 2N in H₂ O, 2mmoles). The reaction mixture was refluxed for 1 hr when thin layerchromatography showed complete reaction. The mixture was cooled to roomtemperature, diluted with water, and extracted with methylene chloride(2×15 mL). The combined extracts were washed with brine, dried overMgSO₄, and the solvent removed at reduced pressure to afford 170 mg(72%) of product as the methyl ester. The methyl ester was thensuspended in 2 mL of ethanol, treated with 5 eq of aqueous NaOH and themixture was stirred at room temperature for 1 hr. At this time, thereaction mixture was quenched with 2N HCl, diluted with ethyl acetate,and the layers were separated. The aqueous layer was extracted withethyl acetate, and the combined extracts were washed with brine, driedover MgSO₄, and the solvent removed at reduced pressure to afford 140 mgof product.

TLC (methylene chloride--10% methanol) R_(f) 0.17; ¹ H NMR (CDCl₃ /CD₃OD) δ 7.65 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.6 Hz, 2H), 7.18(d, J=3.6 Hz,1H), 6.68 (d, J=3.6 Hz, 1H). ##STR366## Step 2

A suspension of the product of step 1 (1.42 g, 6.38 mmoles) in methylenechloride was treated with oxalyl chloride (3.5 mL, 2M in CH₂ Cl₂, 7.00mmoles) and one drop of DMF. The mixture was refluxed for 1 hr underargon. At this time, the mixture was cooled to 0° C. and cannulated intoan ice cold solution of diazomethane (50 mL, 0.6M in Et₂ O, 30 mmoles).The reaction mixture was allowed to stir at 0° C. for 1 hr before it wasquenched with HCl (30 mL, 1N in Et₂ O, 30 mmoles). The mixture was thenstirred at room temperature for 1.5 hr, transferred to a separatoryfunnel with ethyl acetate, washed with saturated sodium bicarbonatesolution, brine, and dried over MgSO₄. The crude product waschromatographed with 0-30% ethyl acetate in hexanes to afford 1.28 g(79%) of product.

TLC (hexanes--10% ethyl acetate) R_(f) 0.13; ¹ H NMR (CDCl₃) δ 7.73 (d,J=8.6 Hz, 2H), 7.46-7.40 (m, 3H), 6.83 (d, J=3.6 Hz, 1H), 4.60 (s, 2H);¹³ C NMR (CDCl₃) δ 179.73, 157.43, 149.64, 135.64, 129.31, 127.39,126.32, 121.12, 108.15, 44.88. ##STR367## Step 3--Preparation of Example251

The procedure was analogous to that of Example 250 except the product ofstep 2 was used instead of the corresponding product from the Example250 preparation.

EXAMPLE 251

MP 129°-130° C.; TLC (methylene chloride--10% methanol) R_(f) 0.47; ¹ HNMR (CDCl₃) δ 7.72 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.30-7.16(m, 6H), 6.77 (d, J=3.6 Hz, 1H), 3.34 (dd, J₁ =16.7 Hz, J₂ =8.3 Hz, 1H),3.17-3.08 (m, 1H), 2.98 (dd, J₁ =17.3 Hz, J₂ =4.8 Hz, 1H), 2.66 (t,J=6.9 Hz, 2H), 1.85-1.65 (m, 4H); MS (FAB-LSIMS) 397 M+H!⁺ ; ElementalAnalysis calcd. for C₂₃ H₂₁ ClO₄ C 69.61, H 5.33, Cl 8.93; ElementalAnalysis found. C 69.47, H 5.43, Cl 8.71.

Biological Protocols and in vitro Test Data

Preparation of Gelatinase-B (92 kDa, MMP-9):

MMP-9 was isolated modifying the previously described procedures ofHibbs et al (J. Biol. Chem., 260, 2493-2500, 1984) and Wilhelm et al (J.Biol. Chem., 264, 17213-17221, 1989). Briefly, polymorphonuclearleukocytes (PMN) preparations were isolated as described above from 3 ormore units of freshly drawn whole blood obtained from the New York BloodCenter (N.Y., N.Y.). Cells were resuspended in phosphate buffered saline(PBS) containing 100 ng/ml phorbol myristate acetate (PMA) in thepresence of 50 mM diisopropylfluorophospate (DFP), 1 μg/ml leupeptin andaprotinin, and 1 mg/ml catalase for 1 hr at 37° C. Supernatants werecollected by centrifugation (300×g) and the samples were frozen at -70°C. All chromatographic methods were performed at 4° C. Thawed sampleswere concentrated 5-fold using an Amicon chamber equipped with a YM-10membrane. The concentrate was pressure dialyzed against 0.02M Tris-HCl,0.1M NaCl, 1 mM CaCl₂, 1 μM ZnCl₂, 0.001% Brij-35, 0.02% sodium azide(NaN₃), pH 7.5 and applied to DEAE ion exchange chromatography resinwhich was previously equilibrated with the same buffer at a flow rate of0.4 ml/min. The column was extensively washed with the same buffer andgelatinase was eluted as 4 ml fractions from the column with 0.02MTris-HCl, 0.5M NaCl, 1 mM CaCl₂, 1 μM ZnCl₂, 0.001% Brij-35, 0.02% NaN₃,pH 7.5. Gelatinase containing fractions were observed by gelatinzymography (see below), loaded onto a gelatin agarose affinity resin andwashed with the same buffer. Gelatinase activity was eluted at a flowrate of 1 ml/min from the column as 1 ml fractions with 0.02M Tris-HCl,1M NaCl, 1 mM CaCl₂, 1 μM ZnCl₂, 0.001% Brij-35, 0.02% NaN₃, pH 7.5containing 10% dimethyl sulfoxide (DMSO). The fractions containinggelatinase activity were pooled and dialyzed against 0.005M Tris-HCl, 5mM NaCl, 0.5 mM CaCl₂, 0.1 μM ZnCl₂, 0.001% Brij-35, pH 7.4. The proteincontent associated with material was determined with a micro-BCA assay(Pierce, Rockford, Ill.), lyophilized and reconstituted to a desiredworking concentration (100 μg/ml).

Thiopeptilide MMP-9 Inhibition Assay:

Progelatinase (10 μg/ml) isolated from human PMNs (described above) wasactivated with 1 mM 4-aminophenylmercuric acetate (APMA) in 50 mMTris-HCl, 200 mM NaCl, 5 mM CaCl₂, 0.001% Brij-35, pH 7.6 at 37° C. for16 hr. The activated enzyme was dialyzed against the above buffer toremove APMA. The thiopeptolide spectrophotometric (Weingarten, H.,Feder, J., Anal. Biochem., 147, 437-440, 1985) substrate hydrolysisassay was modified to a micro-assay format. Spectrophotometric analysisof MMP-9 activity required a 1000-fold dilution of activated MMP-9 (10ng/ml, 0.14 nM) in assay buffer comprised of 50 mM4-(2-hydroxyethyl)1-piperazine ethane sulfonic acid (HEPES), 0.15M NaCl,10 mM CaCl₂, 0.001% Brij-35, pH 6.5 between 100 and 1000-fold for enzymeassays. Reaction mixtures for inhibitor studies contained 1 mMAc-Pro-Leu-Gly-S-Leu-Leu-Gly-o-ethyl thiopeptolide substrate dissolvedin HEPES assay buffer pH 6.5, along with 0.5 mM5,5'-dithio-bis-(nitrobenzoic acid), drug concentrations ranging from0.5 nM to 5 μM and activated enzyme (10-100 ng) in a total volume of 130μl. The hydrolysis of substrate was monitored at 405 nm using anautomated plate reader (Molecular Devices, Menlo Park, Calif.). Enzymemediated substrate hydrolysis was corrected for non-enzymatic hydrolysisof the substrate by the subtraction of values from control samplesincubated in the absence of enzyme. Drug efficacy was reported as thepercent inhibition of enzyme activity calculated as:

(Control Values-Treated Values)/Control Values×100

Active compounds with a demonstrated 30% inhibition of enzyme activityor greater were tested further at varying concentrations (0.5 nM-5 μM)and linear regression analysis of percent inhibition versus log drugconcentration was used to obtain IC₅₀ values. Two way analysis ofvariance was used to determine significance between individual testgroups.

Expression and Purification of Recombinant Truncated Prostromelysin(MMP-3):

Truncated Prostromelysin-257 was expressed in a soluble form in E.colias described by Marcy et al., Biochemistry, 30, 6476-6483, 1991. Solubletruncated prostromelysin was purified by a modification of themonoclonal antibody affinity chromatography method described by Housleyet al., J. Biol. Chem., 268, 4481-87, 1993.

Primary Thiopeptilide MMP-3 Inhibition Assay:

Enzyme: recombinant stromelysin expressed in E.coli and purified asdescribed above. Truncated stromelysin was heat activated as describedby Kokalitis et al., Biochem. J., 276, 217-221, 1991. The protocols forthe assay of compounds as stromelysin inhibitors was the same as thatused for MMP-9 except that the assay buffer was 50 mM MES, pH 6.5containing 150 mM NaCl, 10 mM CaCl2, 0.005% Brij, and 1% DMSO. Theenzyme concentration was 13 nM stromelysin. The substrate concentrationwas 658 micromolar (μM) and our drug concentrations were the same aswith the MMP-9 assay.

Secondary P218 Quenched fluorescence Assay for MMP-3 Inhibition:

This assay was originally described by Knight et al., FEBS Letters, 296,263-266, 1992, for a related substrate. The assay is run continuously ina 3.0 ml cuvette using a Perkin-Elmer LS 50 B Spectrofluorimeter at 25°C. in a final volume of 2.0 mls. P218 substrate (10 mM) in 100% DMSO isdiluted to a final concentration of 2.0 micromolar (μM) into assaybuffer: 50 mM MES, pH 6.5 containing 150 mM NaCl, 10 mM CaCl2, 0.005%Brij-35, and 1% (v/v) DMSO. Test compounds (10 mM) in DMSO are dilutedin assay buffer at an initial concentration of 10 to 100 micromolar.These are diluted to a final concentration in the assay from 10 nM to 1μM depending upon their potency previously determined in primarythiopeptilide assay described above. The reaction is initiated by theaddition of recombinant stromelysin (MMP-3) at a final concentration of1.0 nM. Upon peptide cleavage, the fluorescent MCA group was detectedusing an excitation wavelength of 328 nanometers and an emissionwavelength of 393 nanometers. The assay is linear from 0.2 to 5 nM MMP-3concentration and percent inhibition is calculated as described abovefor the primary thiopeptilide assay and IC₅₀ values are determined by alinear regression analysis of percent inhibition versus log drugconcentration.

The peptide sequence of the MCA substrate, hereinafter designated P218,is shown below:

MCA-Pro-Lys-Pro-Leu-Ala-Leu-DPA-Ala-Arg-NH₂

P218

For MMP-3, this substrate has a K_(m) of 16 μM at pH 6.5 and akcat/K_(m) value of 56,000M⁻¹ sec⁻¹.

Secondary P218 Quenched fluorescence Assay for MMP-2 Inhibition:

Gelatinase A (MMP-2) was prepared using a vaccinia expression systemaccording to the method of R. Fridman, et al., J. Biol. Chem., 267,15398 (1992). Inhibition assays with MMP-2 were carried out as describedfor MMP-3 above using 0.2 nM final enzyme concentration and the P218substrate. MMP-2 has a turnover number of 400,000 in this assay. Initialvelocities (nM/sec.) never exceeded 5% of the total substrate in theseexperiments.

Biaryl Matrix Metalloprotease Inhibitors

Assay Data for the Invention and Reference compounds:

All IC₅₀ values are expressed as nM. When "I=x %" is shown, x representsthe % inhibition at 5 μM. When "x (n)" is shown, x is the average IC₅₀value of n separate determinations.

    ______________________________________            MMP-3     MMP-3     MMP-9:  MMP-2            Thiopeptilide                      Fluorogenic                                Thiopeptilide                                        Fluorogenic    Ex. #   IC.sub.50 IC.sub.50 IC.sub.50                                        IC.sub.50    ______________________________________    fenbufen          Inactive  I = 2%  1,000    1       486 (7)   805 (2)   1,000    2       270                 2,200    3       I = 13%             I = 0%    4       379       480       2,700    5       I = 11%             I = 19%    6       2,100               I = 38%    7       690                 2,100    8       I = 26%             I = 0%    9       I = 0%              I = 3%    10      I = 1%              I = 0%    11      I = 14%             I = 0%    12      I = 17%             I = 0%    13      I = 27%             I = 3%    14      440       570       1,200    15      2,000               I = 0%    16      620                 3,100    17      I = 35%             I = 0%    18      I = 0.3%            I = 9%    19      550                 1,200    20      I = 32%             I = 34%    21      750                 1,200    22      I = 11%             I = 15%    23      790                 1,200    24      I = 56%             I = 29%    25      I = 58%             6,000    26      2,600               2,400    27      5,000    28      I = 0%    29      I = 0%              I = 0%    30      I = 24%             I = 0%    31      I = 14%             I = 0%    32      I = 40%             I = 0%    33      950                 I = 43%    34      I = 28%             I = 44%    35      I = 8%              I = 25%    36      620       240       4,300    37      I = 9%              I = 0%    38      10,000              I = 10%    39      I = 16%             I = 4%    40      121 (4)             50    41      118 (3)   260       500    42                48                21    43    44                1,970             1,150    45                I = 43%           I = 56%    46      700                 4,000    47      560                 I = 22%    48      I = 53%             I = 15%    49      750                 I = 13%    50      630                 800    51      170                 100    52      76 (2)              37    53      950                 800    54      190                 700    55      170                 110    56      310                 700    57      I = 16%             I = 22%    58      1,200               1,500    59      I = 33%             2,000    60      600                 180    61      I = 35%             I = 22%    62      400                 4,500    63      980                 500    64      300                 I = 29%    65      840                 I = 47%    66      I = 7%              I = 11%    67      150                 780    68      280                 300    69      220                 600    70      2,300               I = 38%    71      78                  82 (2)    72      1,000               1,800    73      I = 24%             I = 7%    74      310                 1,200    75      I = 12%             I = 9%    76      470                 800    77      I = 30%             I = 12%    78      I = 23%             I = 9%    79      720                 1,400    80      150                 100 (2)    81      37                  I = 44% (3)    82      168 (4)             I = 30%    83      111 (4)             480    84      I = 36%             I = 11%    85      174                 700    86      I = 60%             I = 26%    87      244 (11)  120 (3)   285 (2) 25 (2)    88      I = 39%             I = 31%    89      145 (4)   80 (2)    190     28 (2)    90      150                 240    91      2,800 (2)           2,800    92      590                 3,800    93      440                 2,200    94      760                 1,800    95      380                 I = 60%    96      1,000               I = 45%    97      403 (2)    98      I = 43%    99      180 (2)             I = 28%    100     1,600               I = 50% (2)    101     105 (2)             1,800    102     600 (2)    103     310 (2)    104     230       1,200     2,900    105     310 (2)             900    106     112 (4)             2,600 (2)    107     160 (2)             200    108     270                 360    109     330                 290    110     I = 7%              I = 17%    111     270                 710    112     280                 I = 41%    113     220                 I = 31%    114     170                 383 (3)    115     757                 1,500    116     151                 1,300    117     530                 600    118     153 (3)   150 (2)   2,450 (2)                                        40 (2)    119     115 (2)   62        750    120     I = 31%             I = 20%    121     236 (12)  180 (2)   438 (5) 20 (2)    122     I = 55%    123     117 (2)   92        197 (3) 26 (2)    124     I = 23%             I = 21%    125     I = 14%    126     I = 17%    127     830    128     1,600    129     170                 200    130     640                 2,300    131     340                 800    132     250                 500    133     247 (3)             1,200    134     213 (3)             215 (2)    135     87 (3)              170    136     950 (2)             417 (3)    137     180 (2)             290 (3)    138     140 (2)             1,050 (2)    139     340                 390 (2)    140     500                 205 (2)    141     440                 280    142     650                 390 (2)    143     2,500               I = 41%    144     170                 2,200    145     1,300               1,200    146     770                 590    147     83                  245 (2)    148     170                 435 (2)    149     260                 600    150     190                 950    151     240                 2,400    152     610                 1,800    153     930                 580    154     680                 550    155     310                 550    156     720                 255 (2)    157     220                 360 (2)    158     360                 800    159     300                 900    160     250                 550    161     280                 820    162     150                 200 (2)    163     339 (2)             4,800    164     144 (2)             600    165     1,600    166     2,000    167     2,000    168     920    169     490                 I = 53%    170     96 (2)              300 (2)    171     195 (2)             340 (2)    172     490                 1,300    173     360                 850    174     79 (4)    27 (1)    600     7 (1)    175     125 (2)             800    176     640 (3)             7,500    177     293 (3)             2,900    178     I = 0%              I = 21%    179     950                 2,000    180     600                 3,000    181     800                 2,100    182     820                 2,100    183     I = 10%             I = 27%    184     I = 19%    185     520                 I = 16%    186     900                 I = 20%    187     227                 215 (2)    188     640                 10,000    189     95 (2)              76 (2)    190     I = 33%             I = 21%    191     I = 48%             I = 31%    192     2,900               I = 42%    193     250                 650    194     38 (3)              1.8 (2)    195     330                 I = 62%    196     140                 510    197     I = 2%              I = 0%    198     2,400               7,000    199     I = 10%             I = 1%    200     2,500               I = 21%    201     I = 19%             I = 0%    202     I = 26%             I = 3%    203     I = 40%             I = 46%    204     348 (4)             910 (2)    205     I = 35%             I = 15%    206     437 (3)             2,700 (3)    207     I = 21%             I = 12%    208     I = 16%             I = 0%    209     47 (8)    14 (4)    56 (5)  4 (2)    210     99                  600    211     26 (10)   12 (2)    25 (4)    212                         640 (3)    213     73                  62 (2)    214    215     310                 1,400    216     55                  42 (2)    217     470                 1,800    218     150                 550    219     33                  108 (2)    220    221     50                  850    222     80                  32 (2)    223     340                 700    224     36 (4)    225     66 (4)    226     98 (2)    227     140 (2)    228     I = 55%             12,000    229     I = 49%             I = 45%    230     I = 58%             8,000    231     I = 9%              I = 16%    232     I = 15%             I = 18%    233     I = 62% (2)         I = 25%    234     1,400               600    235     I = 37%             I = 41%    236     I = 42%             6,000    237     I = 55%             6,000    238     I = 20%             I = 2%    239     I = 24%             I = 32%    240     1,700               1,500    241     I = 14%             I = 21%    242     2,400               3,800    243     360                 700    244     500                 680    245     I = 11%             I = 14%    246     5,000               I = 30%    247     6,000               I = 34%    248     I = 12%             I = 0%    249     I = 31%             I = 36%    250     550                 330    251     I = 4%              I = 20%    ______________________________________

It should be noted in the above table that a biaryl portion is necessaryfor significant MMP inhibitory activity--see, for example, biphenylexample 1 in comparison to reference phenyl example 22 or biphenylexample 130 in comparison to reference phenyl example 178. It is alsonoted that reference phenoxyphenyl example 183 is only of very lowpotency. It is also demonstrated that, while a 4-substituent on ring Ais not essential for potency, it does lead to significant improvedpotency--see low potency unsubstituted examples 13 and 91 in comparisonto chlorine substituted examples 1 and 87. It is also clear thatincreased size of substituent R⁶ on portion E leads to increasedactivity--see unsubstituted example 6 compared to methyl substitutedexample 33 compared to ethyl substituted example 92. This is also shownin a comparison of example 208 in which E represents a cyclopropane ringin comparison to much more active example 206 with a cyclobutane ring.Only minor activity, at best, is observed when the compound is neithersubstituted on biphenyl nor on portion E such as in reference compoundFenbufen (first entry of the table).

The exemplary compounds described above have the following chemicalnames, according to the Chemical Abstracts naming system.

    __________________________________________________________________________    EXAMPLE    COMPOUND    NUMBER:           Chemical Abstracts (CA) Index Name    __________________________________________________________________________    1:      1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-(2-methylpropyl)           -γ-oxo-    2:      1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-(2-methylpropyl)           -γ-oxo-, (S)-    3:      1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-(2-methylpropyl)           -γ-oxo-, (R)-    4:      1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-β-(2-methylpropy1)-           γ-oxo-, (S)-    5:      1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-β-(2-methylpropy1)-           γ-oxo-, (R)-    6:      1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-    7:      1,1'-Biphenyl!-4-butanoic acid, 4'-bromo-γ-oxo-    8:      1,1'-Biphenyl!-4-butanoic acid, 4'-fluoro-γ-oxo-    9:      1,1'-Biphenyl!-4-butanoic acid, 2'-fluoro-γ-oxo-    10:     1,1'-Biphenyl!-4-butanoic acid, 2'-chloro-γ-oxo-    11:     1,1'-Biphenyl!-4-butanoic acid, 2',4'-difluoro-γ-oxo-    12:     1,1'-Biphenyl!-4-butanoic acid, 3'-chloro-γ-oxo-    13:     1,1'-Biphenyl!-4-butanoic acid, α-(2-methylpropyl)-γ-o           xo-    14:     1,1'-Biphenyl!-4-butanoic acid, 4'-bromo-α-(2-methylpropyl)-           γ-oxo-    15:     1,1'-Biphenyl!-4-butanoic acid, 4'-fluoro-α-(2-methylpropyl)           -γ-oxo-    16:     1,1'-Biphenyl!-4-butanoic acid, 4'-ethyl-α-(2-methylpropyl)-           γ-oxo-    17:     1,1'-Biphenyl!-4-butanoic acid, 2'-fluoro-α-(2-methylpropyl)           -γ-oxo-    18:     1,1'-Biphenyl!-4-butanoic acid, 2'-chloro-α-(2-methylpropyl)           -γ-oxo-    19:     1,1'-Biphenyl!-4-butanoic acid, 4'-methoxy-α-(2-methylpropyl           )-γ-oxo-    20:     1,1'-Biphenyl!-4-butanoic acid, 2',4'-difluoro-α-(2-methylpr           opyl)-γ-oxo-    21:     1,1'-Biphenyl!-4-butanoic acid, 4'-methyl-α-(2-methylpropyl)           -γ-oxo-    22:    Benzenebutanoic acid, 4-chloro-α-(2-methylpropyl)-γ-oxo           -    23:     1,1'-Biphenyl!-4-butanoic acid, α-(2-methylpropyl)-γ-o           xo-4'-pentyl-    24:     1,1'-Biphenyl!-4-butanoic acid, 4'-hydroxy-α-(2-methylpropyl           )-γ-oxo-    25:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-β-methylene-γ           -oxo-    26:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-hydroxy-α-           (2-methylpropyl)-    27:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-hydroxy-α-           (2-methylpropyl)-    28:    2(3H)-Furanone, 5-(4'-chloro 1,1'-biphenyl!-4-yl)dihydro-3-(2-methy           lpropyl)-    29:    2(3H)-Furanone, 5-(4'-chloro 1,1'-biphenyl!-4-yl)dihydro-3-(2-methy           lpropyl)-    30:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-methylene-.gamma           .-oxo-    31:    Benzenebutanoic acid, 4-methyl-α-methylene-γ-oxo-    32:     1,1'-Biphenyl!-4-butanoic acid, 2'-chloro-α-methylene-.gamma           .-oxo-    33:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-methyl-γ-o           xo-    34:    2-Butenoic acid, 4-(4'-chloro 1,1'-biphenyl!-4-yl)-4-oxo-, (E)-    35:    2-Butenoic acid, 4- 4-(4-chlorophenoxy)phenyl!-4-oxo-, (E)-    36:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-pent           yl-    37:    Ethanone, 1-(4'-chloro 1,1'-biphenyl!-4-yl)-    38:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-hydroxy-α-           methylene-    39:     1,1'-Biphenyl!-4-butanoic acid, 2'-fluoro-γ-hydroxy-    40:     1,1'-Biphenyl!-4-butanoic acid, 4'-iodo-γ-oxo-α-(3-phe           nylpropyl)-    41:     1,1'-Biphenyl!-4-butanoic acid, 4'-iodo-α-(2-methylpropyl)-.           gamma.-oxo-    42:     1,1'-Biphenyl!-4-butanoic acid, 4'-(3-ethoxy-3-oxo-1-propenyl)-.ga           mma.-oxo-α-(3-phenylpropyl)-, (E)-    43:     1,1'-Biphenyl!-4-butanoic acid, 4'-(2-carboxyethenyl)-γ-oxo-           α-(3-phenylpropyl)-, (E)-    44:     1,1'-Biphenyl!-4-butanoic acid, 4'-(3-ethoxy-3-oxopropyl)-α-           (3-phenylpropyl)-    45:     1,1'-Biphenyl!-4-butanoic acid, 4'-(2-carboxyethyl)-α-(3-phe           nylpropyl)-    46:     1,1'-Biphenyl!-4-butanoic acid, 4'-cyano-α-(2-methylpropyl)-           γ-oxo-    47:     1,1'-Biphenyl!-4-butanoic acid, 4'-  (1,1-dimethylethoxy)carbonyl!           amino!-γ-oxo-α-(3-phenylpropyl)-    48:     1,1'-Biphenyl!-4-butanoic acid, 4'-(1,1-dimethylethyl)-γ-oxo           -α-(3-phenylpropyl)-    49:     1,1'-Biphenyl!-4-butanoic acid, 4'-   (1,1-dimethylethoxy)carbonyl           !amino!methyl!-γ-oxo-α-(3-phenylpropyl)-    50:     1,1'-Biphenyl!-4-butanoic acid, 4'-(cyanomethyl)-γ-oxo-.alph           a.-(3-phenylpropyl)-    51:     1,1'-Biphenyl!-4-butanoic acid, 4'-(methylthio)-γ-oxo-.alpha           .-(3-phenylpropyl)-    52:     1,1'-Biphenyl!-4-butanoic acid, 4'-(2-chloroethoxy)-γ-oxo-.a           lpha.-(3-phenylpropyl)-    53:     1,1'-Biphenyl!-4-butanoic acid, 4'-(hydroxymethyl)-γ-oxo-.al           pha.-(3-phenylpropyl)-    54:     1,1'-Biphenyl!-4-butanoic acid, 4'-(2-hydroxyethoxy)-γ-oxo-.           alpha.-(3-phenylpropyl)-    55:     1,1'-Biphenyl!-4-butanoic acid, 4'-ethenyl-γ-oxo-α-(3-           phenylpropyl)-    56:     1,1'-Biphenyl!-4-butanoic acid, 4'-cyano-γ-oxo-α-(3-ph           enylpropyl)-    57:     1,1'-Biphenyl!-4-butanoic acid, γ-oxo-α-(3-phenylpropy           l)-4'-(1H-tetrazol-5-yl)-    58:     1,1'-Biphenyl!-4-butanoic acid, 4'-amino-γ-oxo-α-(3-ph           enylpropyl)-    59:     1,1'-Biphenyl!-4-butanoic acid, 4'-(aminomethyl)-γ-oxo-.alph           a.-(3-phenylpropyl)-    60:     1,1'-Biphenyl!-4-butanoic acid, 4'-(dimethylamino)-γ-oxo-.al           pha.-(3-phenylpropyl)-    61:    2-Pyridinebutanoic acid, 5-(4-ethylphenyl)-α-(2-methylpropyl)           -γ-oxo-    62:     1,1'-Biphenyl!-4-butanoic acid, γ-oxo-α-(3-phenylpropy           l)-4'-(trifluoromethyl)-    63:     1,1'-Biphenyl!-4-butanoic acid, 4'-nitro-γ-oxo-α-(3-ph           enylpropyl)-    64:     1,1'-Biphenyl!-4-butanoic acid, 3',4'-dichloro-α-(2-methylpr           opyl)-γ-oxo-    65:     1,1'-Biphenyl!-4-butanoic acid, 3',4'-dichloro-γ-oxo-α           -(3-phenylpropyl)-    66:     1,1'-Biphenyl!-4-butanoic acid, 3',5'-dichloro-γ-oxo-α           -(3-phenylpropyl)-    67:     1,1'-Biphenyl!-4-butanoic acid, 4'-(acetyloxy)-γ-oxo-α           -(3-phenylpropyl)-    68:    Benzenepentanoic acid, α- 2- 4-(5-chloro-2-thienyl)phenyl!-2-           oxoethyl!-    69:     1,1'-Biphenyl!-4-butanoic acid, 4'-methoxy-γ-oxo-α-(3-           phenylpropyl)-    70:     1,1'-Biphenyl!-4-butanoic acid, 3'-chloro-4'-fluoro-γ-oxo-.a           lpha.-(3-phenylpropyl)-    71:     1,1'-Biphenyl!-4-butanoic acid, 4'-ethoxy-γ-oxo-α-(3-p           henylpropyl)-    72:    Benzenepentanoic acid, α- 2-oxo-2- 4-(3-thienyl)phenyl!ethyl!           -    73:     1,1'-Biphenyl!-4-butanoic acid, 2',4'-dichloro-γ-oxo-α           -(3-phenylpropyl)-    74:     1,1'-Biphenyl!-4-butanoic acid, 4'-formyl-γ-oxo-α-(3-p           henylpropyl)-    75:     1,1'-Biphenyl!-4-butanoic acid, γ-oxo-α-(3-phenylpropy           l)-3',5'-bis(trifluoromethyl)-    76:    Benzenepentanoic acid, α- 2-oxo-2- 4-(2-thienyl)phenyl!ethyl!           -    77:     1,1'-Biphenyl!-4-butanoic acid, γ-oxo-α-(3-phenylpropy           l)-3'-(trifluoromethyl)-    78:     1,1'-Biphenyl!-4-butanoic acid, 2'-formyl-γ-oxo-α-(3-p           henylpropyl)-    79:     1,1'-Biphenyl!-4-butanoic acid, 4'-hydroxy-γ-oxo-α-(3-           phenylpropyl)-    80:     1,1'-Biphenyl!-4-butanoic acid, γ-oxo-α-(3-phenylpropy           l)-4'-propoxy-    81:     1,1'-Biphenyl!-4-butanoic acid, γ-oxo-4'-pentyloxy)-α-           (3-phenylpropyl)-    82:     1,1'-Biphenyl!-4-butanoic acid, 4'-(hexyloxy)-γ-oxo-α-           (3-phenylpropyl)-    83:     1,1'-Biphenyl!-4-butanoic acid, 4'-butoxy-γ-oxo-α-(3-p           henylpropyl)-    84:     1,1'-Biphenyl!-4-butanoic acid, γ-oxo-4'-(3-phenylpropoxy)-.           alpha.-(3-phenylpropyl)-    85:     1,1'-Biphenyl!-4-butanoic acid, 4'-(1-methylethoxy)-γ-oxo-.a           lpha.-(3-phenylpropyl)-    86:     1,1'-Biphenyl!-4-butanoic acid, 4'-(heptyloxy)-γ-oxo-α           -(3-phenylpropyl)-    87:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(3-p           henylpropyl)-    88:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(3-p           henylpropyl)-, (R)-    89:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(3-p           henylpropyl)-, (S)-    90:     1,1'-Biphenyl!-4-butanoic acid, 4'-bromo-γ-oxo-α-(3-ph           enylpropyl)-, (S)-    91:     1,1'-Biphenyl!-4-butanoic acid, γ-oxo-α-(3-phenylpropy           l)-    92:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-ethyl-γ-ox           o-    93:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-prop           yl-    94:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-2-pr           openyl-    95:     1,1'-Biphenyl!-4-butanoic acid, α-butyl-4'-chloro-γ-ox           o-    96:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-2-pr           opynyl-    97:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-heptyl-γ-o           xo-    98:     1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-decyl-γ-ox           o-    99:     1,1'-Biphenyl!-4-butanoic acid, 4'-nitro-γ-oxo-α-(2-ph           enylethyl)-    100:    1,1'-Biphenyl!-4-butanoic acid, 4'-amino-γ-oxo-α-(2-ph           enylethyl)-    101:    1,1'-Biphenyl!-4-butanoic acid, 4'-cyano-γ-oxo-α-(2-ph           enylethyl)-    102:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 2-(2-iodophenyl           )ethyl!-γ-oxo-    103:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 2- 2-(methoxyca           rbonyl)phenyl!ethyl!-γ-oxo-    104:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-phen           yl-    105:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(phe           nylmethyl)-    106:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(2-p           henylethyl)    107:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(4-p           henylbutyl)-    108:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(5-p           henylpentyl)-    109:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(6-p           henylhexyl)-    110:    1,1'-Biphenyl!-4-butanoic acid, α-( 1,1'-biphenyl!-4-ylmethy           l)-4'-chloro-γ-oxo-    111:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(3-p           henyl-2-propenyl)-, (E)-    112:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 3-(4-methylphen           yl)propyl!-γ-oxo-    113:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 3-(4-chlorophen           yl)propyl!-γ-oxo-    114:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 3-(4-methoxyphe           nyl)propyl!-γ-oxo-    115:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 2-(4-methoxyphe           nyl)ethyl!-γ-oxo-    116:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 2-(3-methoxyphe           nyl)ethyl!-γ-oxo-    117:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(3-p           henyl-2-propynyl)-    118:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2,2-dimethyl-           1-oxopropyl)thio!methyl!-γ-oxo-    119:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2,2-dimethyl-           1-oxopropyl)thio!methyl!-γ-oxo-    120:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2,2-dimethyl-           1-oxopropyl)thio!methyl!-γ-oxo-    121:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylthio)methyl!-    122:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-methyl-γ-o           xo-α-(phenylthio)-    123:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylthio)methyl!-, (S)-    124:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylthio)methyl!-, (R)-    125:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylsu1finy1)methyl!-,stereoisomer    126:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylsulfiny1)methyl!-,stereoisomer    127:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylsulfinyl)methyl!-,stereoisomer    128:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylsulfinyl)methyl!-,stereoisomer    129:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (2-           thienylthio)methyl!-    130:    1,1'-Biphenyl!-4-butanoic acid, α- (acetylthio)methyl!-4'-ch           loro-γ-oxo-    131:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-   (4-methoxyphe           nyl)methyl!thio!methyl!-γ-oxo-    132:    1,1'-Biphenyl!-4-butanoic acid, α- (benzoylthio)methyl!-4'-c           hloro-γ-oxo-    133:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-  (p           henylmethyl)thio!methyl!-    134:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (4-hydroxyphen           yl)thio!methyl!-γ-oxo-    135:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-  (2           -phenylethyl)thio!methyl!-    136:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (4-methoxyphen           yl)thio!methyl!-γ-oxo-    137:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-  (3           -phenylpropyl)thio!methyl!-    138:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (4-fluoropheny           l)thio!methyl!-γ-oxo-    139:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (4-chloropheny           l)thio!methyl!-γ-oxo-    140:    1,1'-Biphenyl!-4-butanoic acid, α-  (4-bromophenyl)thio!meth           yl!-4'-chloro-γ-oxo-    141:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (4-methylpheny           l)thio!methyl!-γ-oxo-    142:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (4-ethylphenyl           )thio!methyl!-γ-oxo-    143:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-   4-(1,1-dimeth           ylethyl)phenyl!thio!methyl!-γ-oxo-    144:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- (cyclohexylthio           )methyl!-γ-oxo-    145:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (3,4-dimethoxy           phenyl)thio!methyl!-γ-oxo-    146:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (3,4-dichlorop           henyl)thio!methyl!-γ-oxo-    147:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-   2-(hydroxymet           hyl)phenyl!thio!methyl!-γ-oxo-    148:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2-fluoropheny           l)thio!methyl!-γ-oxo-    149:    1,1'-Biphenyl!-4-butanoic acid, α-  (2-bromophenyl)thio!meth           yl!-4'-chloro-γ-oxo-    150:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2-ethylphenyl           )thio!methyl!-γ-oxo-    151:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-   2-(1-methylet           hyl)phenyl!thio!methyl!-γ-oxo-    152:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (4-           pyridinylthio)methyl!-    153:    1,1'-Biphenyl!-4-butanoic acid, α-   4-(acetylamino)phenyl!t           hio!methyl!-4'-chloro-γ-oxo-    154:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (4-nitrophenyl           )thio!methyl!-γ-oxo-    155:    1,1'-Biphenyl!-4-butanoic acid, α-   4-(2-carboxyethyl)pheny           l!thio!methyl!-4'-chloro-γ-oxo-    156:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- (2-naphthalenyl           thio)methyl!-γ-oxo-    157:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- (1-naphthalenyl           thio)methyl!-γ-oxo-    158:    1,1'-Biphenyl!-4-butanoic acid, α-  (3-bromophenyl)thio!meth           yl!-4'-chloro-γ-oxo-    159:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2-methoxyphen           yl)thio!methyl!-γ-oxo-    160:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2-chloropheny           l)thio!methyl!-γ-oxo-    161:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (3-methylpheny           l)thio!methyl!-γ-oxo-    162:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2-methylpheny           l)thio!methyl!-γ-oxo-    163:    1,1'-Biphenyl!-4-butanoic acid, α-  (2-carboxyphenyl)thio!me           thyl!-4'-chloro-γ-oxo-    164:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (3-methoxyphen           yl)thio!methyl!-γ-oxo-    165:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (3,5-dimethylp           henyl)thio!methyl!-γ-oxo-    166:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-   3           -(trifluoromethyl)phenyl!thio!methyl!-    167:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-   4-(methoxycab           onyl)phenyl!thio!methyl!-γ-oxo-    168:    1,1'-Biphenyl!-4-butanoic acid, α-   4-(carboxymethyl)phenyl           !thio!methyl!-4'-chloro-γ-oxo-    169:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (1-methylethyl           )thio!methyl!-γ-oxo-    170:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (2-hydroxyphen           yl)thio!methyl!-γ-oxo-    171:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (8-           quinolinylthio)methyl!-    172:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (3-chloropheny           l)thio!methyl!-γ-oxo-    173:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-  (3-fluoropheny           l)thio!methyl!-γ-oxo-    174:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-   2-(methoxycar           bonyl)phenyl!thio!methyl!-γ-oxo-    175:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-   2- (methylami           no)carbonyl!phenyl!thio!methyl!-γ-oxo-    176:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(phe           nylthio)-    177:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylmethyl)thio!-    178:   Benzenebutanoic acid, α- (acetylthio)methyl!-4-methyl-γ           -oxo-    179:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-β- (2-t           hienylthio)methyl!-    180:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-β-  (2,2-dimethyl-1           -oxopropyl)thio!methyl!-γ-oxo-    181:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-β- (phe           nylthio)methyl!-    182:    1,1'-Biphenyl!-4-butanoic acid, β- (acetylthio)methy1!-4'-chl           oro-γ-oxo-    183:   Benzenebutanoic acid, α-(acetylthio)-4-(4-chlorophenoxy)-.gam           ma.-oxo-    184:   4-Thiomorpholineacetic acid, α- 2-(4'-chloro 1,1'-biphenyl!-4           -yl)-2-oxoethyl!-,hydrochloride    185:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- (diphenylmethyl           )amino!- γ-oxo-,hydrochloride    186:   4-Morpholineacetic acid, α- 2-(4'-chloro 1,1'-biphenyl!-4-yl)           -2-oxoethyl!-3,5-dimethyl-,hydrochloride    187:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- 2-(           phenylmethoxy)ethyl!-    188:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (tr           imethylsilyl)methyl!-    189:   2H-Isoindole-2-pentanoic acid, α- 2-(4'-chloro 1,1'-biphenyl!           -4-yl)-2-oxoethyl!-1,3-dihydro-1,3-dioxo-    190:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 2-(dimethylamin           o)ethyl!-γ-oxo-,hydrochloride    191:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 2-(diethylamino           )ethyl!-γ-oxo-,hydrochloride    192:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 3-(diethylamino           )propyl!-γ-oxo-,trifluoroacetate    193:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- 3-(methylthio)p           ropyl!-γ-oxo-    194:   2H-Isoindole-2-butanoic acid, α- 2-(4'-chloro 1,1'-biphenyl!-           4-yl)-2-oxoethyl!-1,3-dihydro-1,3-dioxo-    195:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α- (2-methoxyethox           y)methyl!-γ-oxo-    196:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α- (ph           enylmethoxy)methyl!-    197:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α,α-dimethyl           -γ-oxo-    198:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α,β-dimethyl-           γ-oxo-, (R*,R*)-    199:    1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α,β-dimethyl-           γ-oxo-, (R*,S*)-    200:   Cyclohexanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carbo           nyl!-, trans-    201:   Cyclohexanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carbo           nyl!-, cis-    202:   Benzoic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carbonyl!-    203:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-, cis-    204:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-, trans-    205:   Cyclobutanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carbo           nyl!-, cis-    206:   Cyclobutanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carbo           nyl!-, trans-    207:   Cyclopropanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-, cis-    208:   Cyclopropanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-, trans-    209:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5-(phenylthio)-, (1α,2β,5β)-    210:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5-phenylthio)-, (1α,2β,5α)-    211:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5-phenylthio)-,  1S-(1α,2β,5β)!-    212:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5-phenylthio)-,  1R-(1α,2β,5β)!-    213:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5- (4-fluorophenyl)thio!-, (1α,2β,5β)-    214:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5- (4-fluorophenyl)thio!-, (1α,2α,5α)-    215:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5- (4-fluorophenyl)thio!-, (1α,2β,5α)-    216:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5- (2-methylphenyl)thio!-, (1α,2β,5β)-    217:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5- (2-methylphenyl)thio!-, (1α,2α,5α)-    218:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5- (2-methylphenyl)thio!-, (1α,2β,5α)-    219:   Benzoic acid, 2-  2-carboxy-3- (4'-chloro 1,1'-biphenyl!-4-yl)carbo           nyl!cyclopentyl!thio!-, 1-methyl ester, (1α,2β,3α)           -    220:   Benzoic acid, 2-  2-carboxy-3- (4'-chloro 1,1'-biphenyl!-4-yl)carbo           nyl!cyclopentyl!thio!-, 1-methyl ester, (1α,2α,3α           )-    221:   Benzoic acid, 2-  2-carboxy-3- (4'-chloro 1,1'-biphenyl!-4-yl)carbo           nyl!cyclopentyl!thio!-, 1-methyl ester, (1α,2α,3β)           -    222:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5- (4-chlorophenyl)thio!-, (1α,2β,5β)-    223:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5- (4-chlorophenyl)thio!-, (1α,2β,5α)-    224:   Cyclopentanecarboxylic acid, 2- (4'-ethoxy 1,1'-biphenyl!-4-yl)carb           onyl!-5-(phenylthio)-, (1α,2β,5β)-    225:   Cyclopentanecarboxylic acid, 2- (4'-ethoxy 1,1'-biphenyl!-4-yl)carb           onyl!-5-(phenylthio)-, (1α,2β,5α)-    226:   Cyclopentanecarboxyiic acid, 2- (4'-ethoxy 1,1'-biphenyl!-4-yl)carb           onyl!-5-(phenylmethyl)-, (1α,2β,5β)-    227:   Cyclopentanecarboxylic acid, 2- (4'-chloro 1,1'-biphenyl!-4-yl)carb           onyl!-5-(phenylmethyl)-, (1α,2β,5β)-    228:   3-Cyclohexene-1-carboxylic acid, 6- (4'-chloro 1,1'-biphenyl!-4-yl)           carbonyl!-3,4-dimethyl-, trans-    229:   3-Cyclohexene-1-carboxylic acid, 6- (4'-chloro 1,1'-biphenyl!-4-yl)           carbonyl!-,trans-    230:   3-Cyclohexene-1-carboxylic acid, 6- (4'-chloro 1,1'-biphenyl!-4-yl)           carbonyl!-3-methyl-,trans-    231:   Bicyclo 2.2.2!oct-5-ene-2-carboxylic acid, 3- (4'-chloro 1,1'-biphe           nyl!-4-yl)carbonyl!-,(2R*,3R*)-    232:   Bicyclo 2.2.2!octane-2-carboxylic acid, 3- (4'-chloro 1,1'-biphenyl           !-4-yl)carbonyl!-,trans-    233:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-δ-oxo-    234:   Cyclopentaneacetic acid, 1- 2-(4'-chloro 1,1'-biphenyl!-4-yl)-2-oxo           ethyl!-    235:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-β-methyl-δ-o           xo-    236:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-β,β-dimethyl-           δ-oxo-    237:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-β-ethyl-β-met           hyl-δ-oxo-    238:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-α,α-dimethy           l-δ-oxo-    239:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-α-(2-methylpropyl           )-δ-oxo    240:   Cyclohexaneacetic acid, 1- 2-(4'-chloro 1,1'-biphenyl!-4-yl)-2-oxoe           thyl!-    241:   Cyclopentanepropanoic acid, 1- (4'-chloro 1,1'-biphenyl!-4-yl)carbo           nyl!-    242:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-δ-oxo-α-(3-           phenylpropyl)-    243:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-γ-(2-methylpropyl           )-δ-oxo-    244:    1,1'-Biphenyl!-4-pentanoic acid, 4'-chloro-δ-oxo-γ-(3-           phenylpropyl)-    245:   1-Hexanone, 1-(4'-bromo 1,1'-biphenyl!-4-yl)-6-phenyl-3-(1H-tetrazo           l-5-yl)-    246:   Phosphonic acid,  1- 2-(4'-bromo 1,1'-biphenyl!-4-yl)-2-oxoethyl!-4           -phenylbutyl!-    247:   2-Pyrrolidinecarboxamide, 1- 2- 2-(4'-chloro 1,1'-biphenyl!-4-yl)-2           -oxoethyl!-4-methyl-1-oxopentyl!-N-methyl-, (2S)-    248:   Benzenebutanoic acid, 4-(2-methyl-4-oxazolyl)-α-(2-methylprop           yl)-γ-oxo-    249:   Benzenebutanoic acid, α-(2-methylpropyl)-4-(2-methyl-4-thiazo           lyl)-γ-oxo-    250:   2-Thiophenebutanoic acid, 5-(4-chlorophenyl)-γ-oxo-α-(3           -phenylpropyl)-    251:   2-Furanbutanoic acid, 5-(4-chlorophenyl)-γ-oxo-α-(3-phe           nylpropyl)-    __________________________________________________________________________

Other embodiments of the invention will be apparent to the skilled inthe art from a consideration of this specification or practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with the true scope and spiritof the invention being indicated by the following claims.

We claim:
 1. Compounds having matrix metalloprotease inhibitory activityand the generalized formula: ##STR368## wherein (a) T represents asubstituent group, independently selected from the group consisting ofhalogen; alkyl; haloalkyl; alkenyl; alkynyl; --(CH₂)_(p) Q wherein p is0 or an integer of 1-4; -alkenyl-Q wherein said alkenyl moiety comprises2-4 carbons; wherein Q is selected from the group consisting of aryl,heteroaryl, --CN, --CHO, --NO₂, --CO₂ R², --OCOR², --SOR³, --SO₂ R³,--CON(R²)₂, --SO₂ N(R²)₂, --COR², --N(R²)₂, --N(R²)COR², --N(R²)CO₂ R³,--N(R²)CON(R²)₂, --OR⁴, and --SR⁴ ; wherein R² represents H, alkyl,aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl; R³ represents alkyl,aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl; and R⁴ represents H,alkyl, aryl, heteroaryl, arylalkyl, heteroaryl-alkyl, alkenyl, alkynyl,haloalkyl, acyl, or alkyleneoxy or polyalkyleneoxy terminated with H,alkyl, or phenyl;and with the proviso that unsaturation in a moietywhich is attached to Q or which is encompassed by Q is separated fromany N, O, or S of Q by at least one carbon atom; and x is 0, 1, or 2;(b)D represents ##STR369## (c) R⁶ is selected from the group consisting of:aryl, provided that x is 1 or 2;arylalkyl; heteroaryl-alkyl;aryl-substituted alkenyl; heteroary-substituted alkenyl;aryl-substituted alkynyl; heteroaryl-substituted alkynyl; and with thefurther proviso that--aryl or heteroaryl portions of any of said T or R⁶groups optionally may bear up to two substituents selected from thegroup consisting of --(CH₂)_(y) C(R¹¹)(R¹²)OH, --(CH₂)_(y) OR¹¹,--(CH₂)_(y) SR¹¹, --(CH₂)_(y) S(O)R¹¹, --(CH₂)_(y) S(O)₂ R¹¹,--(CH₂)_(y) SO₂ N(R¹¹)₂, --(CH₂)_(y) N(R¹¹)₂, --(CH₂)_(y) N(R¹¹)COR¹²,--OC(R¹¹)₂ O-- in which both oxygen atoms are connected to the arylring, --(CH₂)_(y) COR¹¹, --(CH₂)_(y) CON(R¹¹)₂, --(CH₂)_(y) CO₂ R¹¹,--(CH₂)_(y) OCOR¹¹, --halogen, --CHO, --CF₃, --NO₂, --CN, and --R¹²,whereiny is 0-4; R¹¹ represents H or lower alkyl; and R¹² representslower alkyl; and (d) G represents --M, ##STR370## wherein M represents--CO₂ H, --CON(R¹¹)₂, or --CO₂ R¹² ; and R¹³ represents any of the sidechains of the 19 noncyclic naturally occurring amino acids; andpharmaceutically acceptable salts thereof.
 2. A compound of claim 1wherein said D unit is a carbonyl group.
 3. A compound of claim 1wherein said G unit is --CO₂ H.
 4. A compound of claim 1 wherein arylportions of aryl-containing T and R⁶ moieties contain only carbon in therings.
 5. A compound of claim 4 having the formula ##STR371## wherein xis 1 or 2; andone substituent T is located on the 4- position of thephenyl ring to which it is attached, relative to the bond of attachmentbetween the two phenyl rings.
 6. A composition having matrixmetalloprotease inhibitory activity, comprising a compound of claim 1and a pharmaceutically acceptable carrier.
 7. A method of treating amammal to achieve an effect, wherein the effect is: alleviation ofosteoarthritis, rheumatoid arthritis, septic arthritis, periodontaldisease, corneal ulceration, proteinuria, aneurysmal aortic disease,dystrophobic epidermolysis bullosa, conditions leading to inflammatoryresponses, osteopenias mediated by MMP activity, tempero mandibularjoint disease, or demyelinating diseases of the nervous system;retardation of tumor metastasis or degenerative cartilage loss followingtraumatic joint injury; reduction of coronary thrombosis fromatherosclerotic plaque rupture; or improved birth control; the methodcomprising administering an amount of a compound of claim 1 which iseffective to inhibit the activity of at least one matrix metalloproteasein said mammal; thereby to achieve said effect.
 8. Compounds havingmatrix metalloprotease inhibitory activity and the generalized formula:##STR372## wherein (a) each T represents a substituent group,independently selected from the group consisting of:the halogens --F,--Cl, --Br, and --I; alkyl of 1-10 carbons; haloalkyl of 1-10 carbons;alkenyl of 2-10 carbons; alkynyl of 2-10 carbons; --(CH₂)_(p) Q ,whereinp is 0 or an integer 1-4, and --alkenyl-Q, whereinsaid alkenylmoiety comprises 2-4 carbons; and Q is selected from the groupconsisting of aryl of 6-10 carbons, heteroaryl comprising 4-9 carbonsand at least one N, O, or S heteroatom, --CN, --CHO, --NO₂, --CO₂ R²,--OCOR², --SOR³, --SO₂ R³, --CON(R²)₂, --SO₂ N(R²)₂, --C(O)R², --N(R²)₂,--N(R²)COR², --N(R²)CO₂ R³, --N(R²)CON(R²)₂, --CHN₄, --OR⁴, and --SR⁴ ;whereinR² represents H; alkyl of 1-6 carbons; aryl of 6-10 carbons;heteroaryl comprising 4-9 carbons and at least one N, O, or Sheteroatom; or arylalkyl in which the aryl portion contains 6-10 carbonsand the alkyl portion contains 1-4 carbons; or heteroaryl-alkyl in whichthe heteroaryl portion comprises 4-9 carbons and at least one N, O, or Sheteroatom and the alkyl portion contains 1-4 carbons; R³ representsalkyl of 1-4 carbons;aryl of 6-10 carbons; heteroaryl comprising 4-9carbons and at least one N, O, or S heteroatom; or arylalkyl in whichthe aryl portion contains 6-10 carbons and the alkyl portion contains1-4 carbons; or heteroaryl-alkyl in which the heteroaryl portioncomprises 4-9 carbons and at least one N, O, or S heteroatom and thealkyl portion contains 1-4 carbons; R⁴ represents H;alkyl of 1-12carbons; aryl of 6-10 carbons; heteroaryl comprising 4-9 carbons and atleast one N, O, or S heteroatom; arylalkyl in which the aryl portioncontains 6-10 carbons and the alkyl portion contains 1-4 carbons;heteroaryl-alkyl in which the heteroaryl portion comprises 4-9 carbonsand at least one N, O, or S heteroatom and the alkyl portion contains1-4 carbons; alkenyl of 2-12 carbons; alkynyl of 2-12 carbons; --(C_(q)H_(2q) O)_(r) R⁵ wherein q is 1-3; r is 1-3; and R⁵ is H provided q isgreater than 1, or alkyl of 1-4 carbons, or phenyl; --(CH₂)_(s) Xwherein s is 2-3 and X is halogen; or --C(O)R² ; and with the provisothat unsaturation in a moiety which is attached to Q or which isencompassed by Q is separated from any N, O, or S of Q by at least onecarbon atom, and x is 0, 1, or 2; (b) D represents ##STR373## (c) R⁶ isselected from the group consisting of: aryl of 6-10 carbons, providedthat x is 1 or 2;arylalkyl wherein the aryl portion contains 6-10carbons and the alkyl portion contains 1-8 carbons; heteroaryl-alkylwherein the heteroaryl portion comprises 4-9 carbons and at least one N,O, or S heteroatom, and the alkyl portion contains 1-8 carbons;aryl-alkenyl wherein the aryl portion contains 6-10 carbons and thealkenyl portion contains 2-5 carbons; heteroaryl-alkenyl wherein theheteroaryl portion comprises 4-9 carbons and at least one N, O, or Sheteroatom and the alkenyl portion contains 2-5 carbons; aryl-alkynylwherein the aryl portion contains 6-10 carbons and the alkynyl portioncontains 2-5 carbons; heteroaryl-alkynyl wherein the heteroaryl portioncomprises 4-9 carbons and at least one N, O, or S heteroatom and thealkynyl portion contains 2-5 carbons; and with the further provisothataryl or heteroaryl portions of any of said T or R⁶ groups optionallymay bear up to two substituents selected from the group consisting of--(CH₂)_(y) C(R¹¹)(R¹²)OH, --(CH₂)_(y) OR¹¹, --(CH₂)_(y) SR¹¹,--(CH₂)_(y) S(O)R¹¹, --(CH₂)_(y) S(O)₂ R¹¹, --(CH₂)_(y) SO₂ N(R¹¹)₂,--(CH₂)_(y) N(R¹¹)₂, --(CH₂)_(y) N(R¹¹)COR¹², --OC(R¹¹)₂ O-- in whichboth oxygen atoms are connected to the aryl ring, --(CH₂)_(y) COR¹¹,--(CH₂)_(y) CON(R¹¹)₂, --(CH₂)_(y) CO₂ R¹¹, --(CH₂)_(y) OCOR¹¹,--halogen, --CHO, --CF₃, --NO₂, --CN, and --R¹², whereiny is 0-4; R¹¹represents H or alkyl of 1-4 carbons; and R¹² represents alkyl of 1-4carbons; and (d) G represents --M, ##STR374## wherein M represents --CO₂H, --CON(R¹¹)₂, or --CO₂ R¹² ; andR¹³ represents any of the side chainsof the 19 noncyclic naturally occurring amino acids; andpharmaceutically acceptable salts thereof.
 9. A compound of claim 8wherein said D unit is a carbonyl group.
 10. A compound of claim 8wherein said G unit is --CO₂ H.
 11. A compound of claim 8 wherein arylportions of aryl-containing T and R⁶ moieties contain only carbon in therings.
 12. A compound of claim 11 having the formula ##STR375## whereinx is 1 or 2; andone substituent T is located on the 4-position of thephenyl group to which it is attached, relative to the bond of attachmentbetween the two phenyl rings.
 13. A composition having matrixmetalloprotease inhibitory activity, comprising a compound of claim 8and a pharmaceutically acceptable carrier.
 14. A method of treating amammal to achieve an effect, wherein the effect is: alleviation ofosteoarthritis, rheumatoid arthritis, septic arthritis, periodontaldisease, corneal ulceration, proteinuria, aneurysmal aortic disease,dystrophobic epidermolysis bullosa, conditions leading to inflammatoryresponses, osteopenias mediated by MMP activity, tempero mandibularjoint disease, or demyelinating diseases of the nervous system;retardation of tumor metastasis or degenerative cartilage loss followingtraumatic joint injury; reduction of coronary thrombosis fromatherosclerotic plaque rupture; or improved birth control; the methodcomprising administering an amount of a compound of claim 8 which iseffective to inhibit the activity of at least one matrix metalloproteasein said mammal, thereby to achieve said effect.
 15. A compound of claim1, having the Chemical Abstracts name 1,1'-Biphenyl!-4-butanoic acid,4'-iodo-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoic acid,4'-(3-ethoxy-3-oxo-1-propenyl)-γ-oxo-α-(3-phenylpropyl)-, (E)-;1,1'-Biphenyl!-4-butanoic acid,4'-(methylthio)-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, 4'-(2-chloroethoxy)-γ-oxo-α-(3-phenylpropyl)-; 1.1'-Biphenyl!-4-butanoic acid,4'-(2-hydroxyethoxy)-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-ethenyl-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid,4'-(acetyloxy)-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, 4'-ethoxy-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, γ-oxo-α-(3-phenylpropyl)-4'-propoxy-; 1,1'-Biphenyl!-4-butanoicacid, γ-oxo-4'-(pentyloxy)-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-(hexyloxy)-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-butoxy-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid,4'-(1-methylethoxy)-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, 4'-chloro-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, 4'-chloro-γ-oxo-α-(3-phenylpropyl)-, (S)-;1,1'-Biphenyl!-4-butanoic acid, 4'-bromo-γ-oxo-α-(3-phenylpropyl)-,(S)-; 1,1'-Biphenyl!-4-butanoic acid, 4'-nitro-γ-oxo-α-(2-phenylethyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-cyano-γ-oxo-α-(2-phenylethyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(2-phenylethyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(4-phenylbutyl)-;1,1'-Biphenyl!-4-butanoic acid,4'-chloro-γ-oxo-α-(3-phenyl-2-propenyl)-, (E)-;1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-3-(4-methoxyphenyl)propyl!-γ-oxo-; or 1,1'-Biphenyl!-4-butanoic acid,4'-chloro-α- 2-(3-methoxyphenyl)ethyl!-γ-oxo-.
 16. A compound of claim8, having the Chemical Abstracts name 1,1'-Biphenyl!-4-butanoic acid,4'-iodo-γ-oxo-α-(3-phenylpropyl)-;
 1. 1'-Biphenyl!-4-butanoic acid,4'-(3-ethoxy-3-oxo-1-propenyl)-γ-oxo-α-(3-phenylpropyl)-, (E)-;1,1'-Biphenyl!-4-butanoic acid,4'-(methylthio)-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, 4'-(2-chloroethoxy)-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid,4'-(2-hydroxyethoxy)-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-ethenyl-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid,4'-(acetyloxy)-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, 4'-ethoxy-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, γ-oxo-α-(3-phenylpropyl)-4'-propoxy-; 1,1'-Biphenyl!-4-butanoicacid, γ-oxo-4'-(pentyloxy)-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-(hexyloxy)-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-butoxy-γ-oxo-α-(3-phenylpropyl)-;1,1'-Biphenyl!-4-butanoic acid,4'-(1-methylethoxy)-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, 4'-chloro-γ-oxo-α-(3-phenylpropyl)-; 1,1'-Biphenyl!-4-butanoicacid, 4'-chloro-γ-oxo-α-(3-phenylpropyl)-, (S)-;1,1'-Biphenyl!-4-butanoic acid, 4'-bromo-γ-oxo-α-(3-phenylpropyl)-,(S)-; 1,1'-Biphenyl!-4-butanoic acid, 4'-nitro-γ-oxo-α-(2-phenylethyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-cyano-γ-oxo-α-(2-phenylethyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(2-phenylethyl)-;1,1'-Biphenyl!-4-butanoic acid, 4'-chloro-γ-oxo-α-(4-phenylbutyl)-;1,1'-Biphenyl!-4-butanoic acid,4'-chloro-γ-oxo-α-(3-phenyl-2-propenyl)-, (E)-; 1.1'-Biphenyl!-4-butanoic acid, 4'-chloro-α-3-(4-methoxyphenyl)propyl!-γ-oxo-; or 1,1'-Biphenyl!-4-butanoic acid,4'-chloro-α- 2-(3-methoxyphenyl)ethyl!-γ-oxo-.